U.S. patent number 8,138,347 [Application Number 12/121,891] was granted by the patent office on 2012-03-20 for quinoline derivatives as pi3 kinase inhibitors.
This patent grant is currently assigned to GlaxoSmithKline LLC. Invention is credited to Steven David Knight, Stanley J. Schmidt.
United States Patent |
8,138,347 |
Knight , et al. |
March 20, 2012 |
Quinoline derivatives as PI3 kinase inhibitors
Abstract
Invented is a method of inhibiting the activity/function of PI3
kinases using quinoline derivatives. Also invented is a method of
treating one or more disease states selected from: autoimmune
disorders, inflammatory diseases, cardiovascular diseases,
neurodegenerative diseases, allergy, asthma, pancreatitis,
multiorgan failure, kidney diseases, platelet aggregation, cancer,
sperm motility, transplantation rejection, graft rejection and lung
injuries by the administration of quinoline derivatives.
Inventors: |
Knight; Steven David
(Collegeville, PA), Schmidt; Stanley J. (Collegeville,
PA) |
Assignee: |
GlaxoSmithKline LLC
(Philadelphia, PA)
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Family
ID: |
40088996 |
Appl.
No.: |
12/121,891 |
Filed: |
May 16, 2008 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080300239 A1 |
Dec 4, 2008 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60938761 |
May 18, 2007 |
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Current U.S.
Class: |
546/167; 544/105;
544/12; 544/128 |
Current CPC
Class: |
A61P
1/00 (20180101); A61P 35/04 (20180101); A61P
25/00 (20180101); C07D 285/24 (20130101); C07D
487/04 (20130101); A61K 31/549 (20130101); A61P
31/12 (20180101); C07D 401/04 (20130101); C07D
495/04 (20130101); A61K 31/496 (20130101); A61P
13/12 (20180101); A61P 17/06 (20180101); C07D
413/14 (20130101); A61P 37/08 (20180101); A61P
35/02 (20180101); A61P 9/12 (20180101); A61P
11/00 (20180101); A61P 1/18 (20180101); A61P
19/04 (20180101); A61P 43/00 (20180101); A61P
21/00 (20180101); C07D 417/14 (20130101); A61P
9/10 (20180101); A61P 25/28 (20180101); A61K
31/4709 (20130101); A61P 9/00 (20180101); A61P
11/06 (20180101); A61P 35/00 (20180101); A61P
7/02 (20180101); A61P 19/02 (20180101); C07D
498/04 (20130101); A61P 37/02 (20180101); A61K
31/5377 (20130101); A61P 37/00 (20180101); A61K
31/5383 (20130101); A61P 9/08 (20180101); A61P
37/06 (20180101); A61P 29/00 (20180101); C07D
401/14 (20130101); A61P 15/08 (20180101); A61P
31/00 (20180101); C07D 471/04 (20130101); A61K
45/06 (20130101); A61P 9/04 (20180101); A61P
31/04 (20180101); A61P 25/14 (20180101); A61P
1/04 (20180101) |
Current International
Class: |
C07D
285/24 (20060101); C07D 413/14 (20060101); C07D
401/14 (20060101) |
References Cited
[Referenced By]
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|
Primary Examiner: Andres; Janet
Assistant Examiner: Rozof; Timothy R
Attorney, Agent or Firm: Peng; Tony W. Gimmi; Edward R.
Parent Case Text
This application claims the benefit of U.S. Provisional Application
No. 60/938,761, filed May 18, 2007, which is herein incorporated by
reference.
Claims
What is claimed is:
1. A compound, which is
2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridi-
nyl}benzenesulfonamide, or a pharmaceutically acceptable salt
thereof.
2. A compound, which is represented by the following structure
##STR00390##
3. A pharmaceutically acceptable salt of a compound of claim 1.
4. A pharmaceutical composition comprising a compound or a
pharmaceutically acceptable salt of claim 1 and a pharmaceutically
acceptable carrier.
Description
FIELD OF THE INVENTION
This invention relates to the use of quinoline derivatives for the
modulation, notably the inhibition of the activity or function of
the phosphoinositide 3' OH kinase family (hereinafter PI3 kinases),
suitably, PI3K.alpha., PI3K.delta., PI3K.beta., and/or PI3K.gamma.,
particularly PI3K.alpha.. Suitably, the present invention relates
to the use of quinolines derivatives in the treatment of one or
more disease states selected from: autoimmune disorders,
inflammatory diseases, cardiovascular diseases, neurodegenerative
diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney
diseases, platelet aggregation, cancer, sperm motility,
transplantation rejection, graft rejection and lung injuries,
particularly cancer.
BACKGROUND OF THE INVENTION
Cellular membranes represent a large store of second messengers
that can be enlisted in a variety of signal transduction pathways.
In regards function and regulation of effector enzymes in
phospholipids signaling pathways, these enzymes generate second
messengers from the membrane phospholipid pools (class I PI3
kinases (e.g. PI3Kalpha) are dual-specificity kinase enzymes,
meaning they display both: lipid kinase (phosphorylation of
phosphoinositides) as well as protein kinase activity, shown to be
capable of phosphorylation of protein as substrate, including
auto-phosphorylation as intramolecular regulatory mechanism. These
enzymes of phospholipids signaling are activated in response to a
variety of extra-cellular signals such as growth factors, mitogens,
integrins (cell-cell interactions) hormones, cytokines, viruses and
neurotransmitters such as described in Scheme I hereinafter and
also by intracellular regulation by other signaling molecules
(cross-talk, where the original signal can activate some parallel
pathways that in a second step transmit signals to PI3Ks by
intra-cellular signaling events), such as small GTPases, kinases or
phosphatases for example. Intracellular regulation can also occur
as a result of aberrant expression or lack of expression of
cellular oncogenes or tumor suppressors. The inositol phospholipid
(phosphoinositides) intracellular signaling pathways begin with
activation of signaling molecules (extra cellular ligands, stimuli,
receptor dimerization, transactivation by heterologous receptor
(e.g. receptor tyrosine kinase) and the recruitment and activation
of PI3K including the involvement of G-protein linked transmembrane
receptor integrated into the plasma membrane.
PI3K converts the membrane phospholipid PI(4,5)P.sub.2 into
PI(3,4,5)P.sub.3 that functions as a second messenger. PI and
PI(4)P are also substrates of PI3K and can be phosphorylated and
converted into PI3P and PI(3,4)P.sub.2, respectively. In addition,
these phosphoinositides can be converted into other
phosphoinositides by 5'-specific and 3'-specific phophatases, thus
PI3K enzymatic activity results either directly or indirectly in
the generation of two 3'-phosphoinositide subtypes that function as
2.sup.nd messengers in intra-cellular signal transduction pathways
(Trends Biochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et
al.: Chem. Rev. 101(8) p. 2365-80 (2001) by Leslie et al (2001);
Annu. Rev. Cell. Dev. Biol. 17p, 615-75 (2001) by Katso et al. and
Cell. Mol. Life. Sci. 59(5) p. 761-79 (2002) by Toker et al.).
Multiple PI3K isoforms categorized by their catalytic subunits,
their regulation by corresponding regulatory subunits, expression
patterns and signaling-specific functions (p110.alpha., .beta.,
.delta. and .gamma.) perform this enzymatic reaction (Exp. Cell.
Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck and Katso et al.,
2001, above).
The closely related isoforms p110.alpha. and .beta. are
ubiquitously expressed, while .delta. and .gamma. are more
specifically expressed in the haematopoietic cell system, smooth
muscle cells, myocytes and endothelial cells (Trends Biochem. Sci.
22(7) p. 267-72 (1997) by Vanhaesebroeck et al.). Their expression
might also be regulated in an inducible manner depending on the
cellular, tissue type and stimuli as well as disease context.
Inducibility of protein expression includes synthesis of protein as
well as protein stabilization that is in part regulated by
association with regulatory subunits.
To date, eight mammalian PI3Ks have been identified, divided into
three main classes (I, II, and III) on the basis of sequence
homology, structure, binding partners, mode of activation, and
substrate preference. In vitro, class I PI3Ks can phosphorylate
phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P),
and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P.sub.2) to
produce phosphatidylinositol-3-phosphate (PI3P),
phosphatidylinositol-3,4-bisphosphate (PI(3,4)P.sub.2, and
phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P.sub.3,
respectively. Class II PI3Ks phosphorylate PI and
phosphatidylinositol-4-phosphate. Class III PI3Ks can only
phosphorylate PI (Vanhaesebrokeck et al., 1997, above;
Vanhaesebroeck et al., 1999, above and Leslie et al, 2001,
above)
##STR00001##
As illustrated in Scheme A above, phosphoinositide 3-kinases
(PI3Ks) phosphorylate the hydroxyl of the third carbon of the
inositol ring. The phosphorylation of phosphoinositides that
generate PtdIns to 3,4,5-trisphosphate (PtdIns(3,4,5)P.sub.3),
PtdIns(3,4)P.sub.2 and PtdIns(3)P produce second messengers for a
variety of signal transduction pathways, including those essential
to cell proliferation, cell differentiation, cell growth, cell
size, cell survival, apoptosis, adhesion, cell motility, cell
migration, chemotaxis, invasion, cytoskeletal rearrangement, cell
shape changes, vesicle trafficking and metabolic pathway (Katso et
al., 2001, above and Mol. Med. Today 6(9) p. 347-57 (2000) by
Stein). G-protein coupled receptors mediate phosphoinositide
3'OH-kinase activation via small GTPases such as G.beta..gamma. and
Ras, and consequently PI3K signaling plays a central role in
establishing and coordinating cell polarity and dynamic
organization of the cytoskeleton--which together provides the
driving force of cells to move. Chemotaxis--the directed movement
of cells toward a concentration gradient of chemical attractants,
also called chemokines is involved in many important diseases such
as inflammation/auto-immunity, neurodegeneration, antiogenesis,
invasion/metastasis and wound healing (Immunol. Today 21(6) p.
260-4 (2000) by Wyman et al.; Science 287(5455) p. 1049-53 (2000)
by Hirsch et al.; FASEB J. 15(11) p. 2019-21 (2001) by Hirsch et
al. and Nat. Immunol. 2(2) p. 108-15 (2001) by Gerard et al.).
Advances using genetic approaches and pharmacological tools have
provided insights into signalling and molecular pathways that
mediate chemotaxis in response to chemoattractant activated
G-protein coupled receptors. PI3-Kinase, responsible for generating
these phosphorylated signalling products, was originally identified
as an activity associated with viral oncoproteins and growth factor
receptor tyrosine kinases that phosphorylates phosphatidylinositol
(PI) and its phosphorylated derivatives at the 3'-hydroxyl of the
inositol ring (Panayotou et al., Trends Cell Biol. 2 p. 358-60
(1992)). However, more recent biochemical studies revealed that
class I PI3 kinases (e.g. class IB isoform PI3K.gamma.) are
dual-specific kinase enzymes, meaning they display both lipid
kinase and protein kinase activity, shown to be capable of
phosphorylation of other proteins as substrates, as well as
auto-phosphorylation as an intra-molecular regulatory
mechanism.
PI3-kinase activation, is therefore believed to be involved in a
range of cellular responses including cell growth, differentiation,
and apoptosis (Parker et al., Current Biology, 5 p. 577-99 (1995);
Yao et al., Science, 267 p. 2003-05 (1995)). PI3-kinase appears to
be involved in a number of aspects of leukocyte activation. A
p85-associated PI3-kinase activity has been shown to physically
associate with the cytoplasmic domain of CD28, which is an
important costimulatory molecule for the activation of T-cells in
response to antigen (Pages et al., Nature, 369 p. 327-29 (1994);
Rudd, Immunity 4 p. 527-34 (1996)). Activation of T cells through
CD28 lowers the threshold for activation by antigen and increases
the magnitude and duration of the proliferative response. These
effects are linked to increases in the transcription of a number of
genes including interleukin-2 (IL2), an important T cell growth
factor (Fraser et al., Science 251 p. 313-16 (1991)). Mutation of
CD28 such that it can no longer interact with PI3-kinase leads to a
failure to initiate IL2 production, suggesting a critical role for
PI3-kinase in T cell activation. PI3K.gamma. has been identified as
a mediator of G beta-gamma-dependent regulation of JNK activity,
and G beta-gamma are subunits of heterotrimeric G proteins
(Lopez-Ilasaca et al., J. Biol. Chem. 273(5) p. 2505-8 (1998)).
Cellular processes in which PI3Ks play an essential role include
suppression of apoptosis, reorganization of the actin skeleton,
cardiac myocyte growth, glycogen synthase stimulation by insulin,
TNF.alpha.-mediated neutrophil priming and superoxide generation,
and leukocyte migration and adhesion to endothelial cells.
Recently, (Laffargue et al., Immunity 16(3) p. 441-51 (2002)) it
has been described that PI3K.gamma. relays inflammatory signals
through various G(i)-coupled receptors and its central to mast cell
function, stimuli in context of leukocytes, immunology includes
cytokines, chemokines, adenosines, antibodies, integrins,
aggregation factors, growth factors, viruses or hormones for
example (J. Cell. Sci. 114(Pt 16) p. 2903-10 (2001) by Lawlor et
al.; Laffargue et al., 2002, above and Curr. Opinion Cell Biol.
14(2) p. 203-13 (2002) by Stephens et al.).
Specific inhibitors against individual members of a family of
enzymes provide invaluable tools for deciphering functions of each
enzyme. Two compounds, LY294002 and wortmannin (cf. hereinafter),
have been widely used as PI3-kinase inhibitors. These compounds are
non-specific PI3K inhibitors, as they do not distinguish among the
four members of Class I PI3-kinases. For example, the IC.sub.50
values of wortmannin against each of the various Class I
PI3-kinases are in the range of 1-10 nM. Similarly, the IC.sub.50
values for LY294002 against each of these PI3-kinases is about
15-20 .mu.M (Fruman et al., Ann. Rev. Biochem., 67, p. 481-507
(1998)), also 5-10 microM on CK2 protein kinase and some inhibitory
activity on phospholipases. Wortmannin is a fungal metabolite which
irreversibly inhibits PI3K activity by binding covalently to the
catalytic domain of this enzyme. Inhibition of PI3K activity by
wortmannin eliminates subsequent cellular response to the
extracellular factor. For example, neutrophils respond to the
chemokine fMet-Leu-Phe (FMLP) by stimulating PI3K and synthesizing
PtdIns (3, 4, 5)P.sub.3. This synthesis correlates with activation
of the respirators burst involved in neutrophil destruction of
invading microorganisms. Treatment of neutrophils with wortmannin
prevents the fMLP-induced respiratory burst response (Thelen et
al., Proc. Natl. Acad. Sci. USA, 91, p. 4960-64 (1994)). Indeed,
these experiments with wortmannin, as well as other experimental
evidence, shows that PI3K activity in cells of hematopoietic
lineage, particularly neutrophils, monocytes, and other types of
leukocytes, is involved in many of the non-memory immune response
associated with acute and chronic inflammation.
##STR00002##
Based on studies using wortmannin, there is evidence that
PI3-kinase function is also required for some aspects of leukocyte
signaling through G-protein coupled receptors (Thelen et al., 1994,
above). Moreover, it has been shown that wortmannin and LY294002
block neutrophil migration and superoxide release. Cyclooxygenase
inhibiting benzofuran derivatives are disclosed by John M. Janusz
et al., in J. Med. Chem. 1998; Vol. 41, No. 18.
It is now well understood that deregulation of onocogenes and
tumour-suppressor genes contributes to the formation of malignant
tumours, for example by way of increase cell growth and
proliferation or increased cell survival. It is also now known that
signaling pathways mediated by the PI3K family have a central role
in a number of cell processes including proliferation and survival,
and deregulation of these pathways is a causative factor a wide
spectrum of human cancers and other diseases (Katso et al., Annual
Rev. Cell Dev. Biol. 2001, 17: 615-617 and Foster et al., J. Cell
Science, 2003, 116: 3037-3040).
Class I PI3K is a heterodimer consisting of a p110 catalytic
subunit and a regulatory subunit, and the family is further divided
into class Ia and Class Ib enzymes on the basis of regulatory
partners and mechanism of regulation. Class la enzymes consist of
three distinct catalytic subunits (p110.alpha., p110.beta., and
p110.delta.) that dimerise with five distinct regulatory subunits
(p85.alpha., p55.alpha., p50.alpha., p85.beta., and p55.gamma.),
with all catalytic subunits being able to interact with all
regulatory subunits to form a variety of heterodimers. Class Ia
PI3K are generally activated in response to growth
factor-stimulation of receptor tyrosine kinases, via interaction of
the regulatory subunit SH2 domains with specific phospho-tyrosine
residues of the activated receptor or adaptor proteins such as
IRS-1. Small GTPases (ras as an example) are also involved in the
activation of PI3K in conjunction with receptor tyrosine kinase
activation. Both p110.alpha. and p110.beta. are constitutively
expressed in all cell types, whereas p110.delta. expression is more
restricted to leukocyte populations and some epithelial cells. In
contrast, the single Class Ib enzyme consists of a p110.gamma.
catalytic subunit that interacts with a p101 regulatory subunit.
Furthermore, the Class Ib enzyme is activated in response to
G-protein coupled receptor (GPCR) systems and its expression
appears to be limited to leukocytes.
There is now considerable evidence indicating that Class Ia PI3K
enzymes contribute to tumourigenesis in a wide variety of human
cancers, either directly or indirectly (Vivanco and Sawyers, Nature
Reviews Cancer, 2002, 2, 489-501). For example, the p110.alpha.
subunit is amplified in some tumours such as those of the ovary
(Shayesteh, et al., Nature Genetics, 1999, 21: 99-102) and cervix
(Ma et al., Oncogene, 2000, 19: 2739-2744). More recently,
activating mutations within p110.alpha. (PIK3CA gene) have been
associated with various other tumors such as those of the colon and
of the breast and lung (Samuels, et al., Science, 2004, 304, 554).
Tumor-related mutations in p85.alpha. have also been identified in
cancers such as those of the ovary and colon (Philp et al., Cancer
Research, 2001, 61, 7426-7429). In addition to direct effects, it
is believed that activation of Class Ia PI3K contributes to
tumourigenic events that occur upstream in signaling pathways, for
example by way of ligand-dependent or ligand-independent activation
of receptor tyrosine kinases, GPCR systems or integrins (Vara et
al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such
upstream signaling pathways include over-expression of the receptor
tyrosine kinase Erb2 in a variety of tumors leading to activation
of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19,
6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh
et al., Nature, 1997, 385, 544-548). In addition, Class Ia PI3Ks
may contribute indirectly to tumourigenesis caused by various
downstream signaling events. For example, loss of function of the
PTEN tumor-suppressor phosphatase that catalyses conversion of
PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range
of tumors via deregulation of PI3K-mediated production of
PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264,
29-41). Furthermore, augmentation of the effects of other
PI3K-mediated signaling events is believed to contribute to a
variety of cancers, for example by activation of AKT (Nicholson and
Andeson, Cellular Signaling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival
signaling in tumor cells, there is also good evidence that class Ia
PI3K enzymes also contributes to tumourigenesis via its function in
tumor-associated stromal cells. For examples, PI3K signaling is
known to play an important role in mediating angiogenic events in
endothelial cells in response to pro-angiogenic factors such as
VEGF (abid et al., Arterioscler, Thromb. Vasc. Biol., 2004, 24,
294-300). As Class I PI3K enzymes are also involved in motility and
migration (Sawyer, Expert Opinion investing. Drugs, 2004, 13,
1-19), PI3K inhibitors are anticipated to provide therapeutic
benefit via inhibition of tumor cell invasion and metastasis.
SUMMARY OF THE INVENTION
This invention relates to novel compounds of Formula (I):
##STR00003## in which R2 is an optionally substituted ring system
selected from a group consisting of: formula (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX) and (X):
##STR00004## R1 is selected from a group consisting of:
heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted
aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is
independently selected from: hydrogen, halogen, acyl, amino,
substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,
substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,
heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl,
alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C,
O, N or S; and/or a pharmaceutically acceptable salt thereof,
provided that in each of formula (V) to (X) at least one X or Y is
not carbon; further provided that R2 is not quinoline or
substituted quinoline. R3 can be attached to any one of the four
open carbon positions.
Suitably, this invention relates to a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
Suitably, this invention relates to a method of treating cancer,
which comprises administering to a subject in need thereof an
effective amount of a compound of Formula (I).
Suitably, this invention relates to a method of treating one or
more disease states selected from: autoimmune disorders,
inflammatory diseases, cardiovascular diseases, neurodegenerative
diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney
diseases, platelet aggregation, sperm motility, transplantation
rejection, graft rejection and lung injuries, which comprises
administering to a subject in need thereof an effective amount of a
compound of Formula (I).
Included in the present invention are methods of co-administering
the present PI3 kinase inhibiting compounds with further active
ingredients.
DETAILED DESCRIPTION OF THE INVENTION
Present compounds of Formula (I) inhibit one or more PI3 kinases.
Suitably, the compounds of formula (I) inhibit PI3K.alpha.. Also,
compounds within the scope of this invention inhibit one or more
PI3 kinases selected from: PI3K.delta., PI3K.beta. and
PI3K.gamma..
Suitably, this invention relates to novel compounds of Formula
(I)(A):
##STR00005## in which R2 is an optionally substituted ring system
selected from a group consisting of: formula (II), (III), and (IV)
as defined above; R1 is selected from a group consisting of:
heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted
aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is
independently selected from: hydrogen, halogen, acyl, amino,
substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,
substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,
heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl,
alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C,
O, N or S; and/or a pharmaceutically acceptable salt thereof;
Suitably, included among the presently invented compounds of
formula (I) are those of formula (I)(B),
##STR00006## wherein R2 is selected from a group consisting of:
formula (V), (VI) and (IX) as defined above; R1 is selected from a
group consisting of: heterocycloalkyl, substituted
heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; each R3 and R4 is independently selected
from: hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl,
substituted C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,
alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,
acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C, O, N or S;
and/or a pharmaceutically acceptable salt thereof, provided that in
each of formula (V), (VI) and (IX) at least one X or Y is not
carbon.
Suitably, included among the presently invented compounds of
formula (I) are those of formula (I)(C),
##STR00007## wherein R2 is selected from a group consisting of:
formula (VII), (VIII) and (X) as defined above; R1 is selected from
a group consisting of: heterocycloalkyl, substituted
heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; each R3 and R4 is independently selected
from: hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl,
substituted C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,
alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,
acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C, O, N or S;
and/or a pharmaceutically acceptable salt thereof, provided that in
each of formula (VII), (VIII) and (X) at least one X or Y is not
carbon.
Suitably, included among the presently invented compounds of
formula (I) are those of formula (I)(D):
##STR00008## in which R2 is an optionally substituted ring system
selected from a group consisting of: formula (II), (III), (IV),
(V), (VI), and (VIII):
##STR00009## R1 is selected from a group consisting of:
heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted
aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is
independently selected from: hydrogen, halogen, acyl, amino,
substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,
substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,
heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl,
alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C,
O, N or S; and/or a pharmaceutically acceptable salt thereof,
provided that in each of formula (V), (VI) and (VIII) at least one
X or Y is not carbon.
Suitably, among the present invention are compounds of Formula
(I)(D), wherein R1 is heteroaryl or substituted heteroaryl; R2 is
selected from a group consisting of: formula (III) and formula
(VI).
Suitably, among the present invention are compounds of Formulas
(I), (I)(A), (I)(B), (I)(C) and (I)(D), wherein R2 is pyridinyl or
substituted pyridinyl.
Suitably, among the present invention are compounds of Formulas
(I), (I)(A), (I)(B), (I)(C) and (I)(D), wherein R2 is not pyridinyl
or substituted pyridinyl.
Suitably, among the present invention are compounds of Formula (I)
wherein R2 is an optionally substituted ring system selected from
the group consisting of Formulas (V)(A), (VI)(A), (VI)(B) and
(IX)(A):
##STR00010## wherein X is C or N; Y is C, O, N or S;
Suitably, among the present invention are compounds of Formula (I)
wherein R2 is an optionally substituted ring system selected from
the group consisting of Formulas (VII)(A), (VIII)(A) and
(X)(A):
##STR00011## wherein X is C or N; Y is C, O, N or S; provided that
at least one Y is not carbon.
Suitably, this invention relates to novel compounds of Formula
(I)(G):
##STR00012## in which each R1, R3, R4 and R5 is independently
selected from: hydrogen, halogen, acyl, amino, substituted amino,
arylamino, acylamino, heterocycloalkylamino, C1-6alkyl, substituted
C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,
alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, acyloxy, and
aryloxy; or R5 is R6, wherein R6 is --SO2NR80 or --NSO.sub.2R80, in
which R80 is selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl,
substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl,
aryl optionally fused with a five-membered ring or substituted with
one to five groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH, wherein n is 0-2, n is 0-2, m is 0-3; or a
pharmaceutically acceptable salt thereof, Suitably, this invention
relates to novel compounds of Formula (I)(H):
##STR00013## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R3 and R4 is independently selected from: hydrogen, halogen,
acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, cyano, hydroxyl and alkoxy; each
R5 is independently selected from: hydrogen, halogen, acyl, amino,
substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, cyano, hydroxyl and alkoxy; or R5
is R6, wherein R6 is --SO2NR80 or --NSO.sub.2R80, in which R80 is
selected from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl,
C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted
C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally
fused with a five-membered ring or substituted with one to five
groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH, wherein n is 0-2, n is 0-2, m is 0-2; or a
pharmaceutically acceptable salt thereof,
Suitably, this invention relates to novel compounds of Formula
(I)(J):
##STR00014## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R3 and R4 is independently selected from: hydrogen, halogen,
acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, cyano, hydroxyl and alkoxy; each
R5 is independently selected from: hydrogen, halogen, acyl, amino,
substituted amino, C1-6alkyl, substituted C1-6alkyl,
C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl,
substituted C3-7heterocycloalkyl, cyano, hydroxyl, alkoxy, nitro;
R6 is --SO2NR80 or --NSO.sub.2R80, in which R80 is selected from a
group consisting of: C1-C6alkyl, C1-C6cycloalkyl,
C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted
C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally
fused with a five-membered ring or substituted with one to five
groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH, wherein n is 0-2; n is 0-2, m is 0-2; or a
pharmaceutically acceptable salt thereof.
Suitably, this invention relates to novel compounds of Formula
(I)(K):
##STR00015## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R5 is independently selected from: hydrogen, halogen, acyl,
amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano,
hydroxyl, alkoxy; n is 0-2, m is 0-1; R6 is --SO2NR80 or
--NSO.sub.2R80, in which R80 is selected from a group consisting
of: C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted
C1-C6alkyl, substituted C1-C6cycloalkyl, substituted
C1-C6heterocycloalkyl, aryl optionally fused with a five-membered
ring or substituted with one to five groups selected from a group
consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,
substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH, wherein n is 0-2; or a pharmaceutically
acceptable salt thereof.
Suitably, this invention relates to novel compounds of Formula
(I)(L):
##STR00016## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R5 is independently selected from: hydrogen, halogen, acyl,
amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano,
hydroxyl, alkoxy; R6 is --SO2NR80 or --NSO.sub.2R80, wherein R80 is
selected from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl,
C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted
C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally
fused with a five-membered ring or substituted with one to five
groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH; n is 0-2, m is 0-1; or a pharmaceutically
acceptable salt thereof.
Suitably, this invention relates to novel compounds of Formula
(I)(M):
##STR00017## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R5 is independently selected from: hydrogen, halogen, acyl,
amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano,
hydroxyl, alkoxy; R6 is --NSO.sub.2R80, wherein R80 is selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl,
C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted
C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally
fused with a five-membered ring or substituted with one to five
groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH; n is 0-2, m is 0-1; or a pharmaceutically
acceptable salt thereof.
Suitably, this invention relates to novel compounds of Formula
(I)(N):
##STR00018## in which R1 is selected from a group consisting of:
heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted
heterocycloalkyl, amino, substituted amino, arylamino, acylamino,
heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;
each R5 is independently selected from: hydrogen, halogen, acyl,
amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano,
hydroxyl, alkoxy; R6 is --SO2NR80, wherein R80 is selected from a
group consisting of: C1-C6alkyl, C1-C6cycloalkyl,
C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted
C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally
fused with a five-membered ring or substituted with one to five
groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH; n is 0-2, m is 0-1 or a pharmaceutically
acceptable salt thereof. Suitably, this invention relates to
compounds of Formulas (I)M) and (I)(N), wherein R1 is selected from
the group consisting of: optionally substituted piperazine,
optionally substituted pyridazine, optionally substituted
morphline, optionally substituted pyrazole, substituted amino and
optionally substituted piperidine. Suitably, this invention relates
to compounds of Formulas (I)M) and (I)(N), wherein R1 is selected
from the group consisting of: optionally substituted piperazine,
optionally substituted pyridazine, optionally substituted
morphline, optionally substituted pyrazole, substituted amino and
optionally substituted piperidine; R80 is selected from a group
consisting of: C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl,
substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted
C1-C6heterocycloalkyl, aryl and substituted aryl. Suitably, this
invention relates to compounds of Formulas (I) M) and (I)(N),
wherein R1 is selected from the group consisting of: optionally
substituted piperazine, optionally substituted pyridazine,
optionally substituted morphline, optionally substituted pyrazole,
substituted amino and optionally substituted piperidine; R80 is
selected from a group consisting of: aryl optionally substituted
with one to five groups selected from a group consisting of:
C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,
trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or
--(CH.sub.2).sub.nCOOH, or heteroaryl optionally substituted with
one to five groups selected from a group consisting of: C1-C6alkyl,
C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl,
alkoxy, oxo, or --(CH.sub.2).sub.nCOOH; n is 0-2. Suitably, this
invention relates to the compound defined in formula (I), (I)(A),
(I)(B), (I)(C), (I) D), (I)(E), (I)(F), (I)(G), (I)(H), (I)(J),
(I)(K), (I)(M) or (I)(N). Suitably, among the present invention are
compounds selected from a group consisting of:
5-[4-(4-pyridinyl)-6-quinolinyl]-1H-indazol-3-amine;
4,4'-di-4-pyridinyl-6,6'-biquinoline;
3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine-
;
2-amino-N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
2-amino-N,N-dimethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonami-
de; 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[4-(4-pyridinyl)-6-quinolinyl]-3-(1H-tetrazol-5-yl)-2-pyridinamine;
6-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;
6-(1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;
3-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine-
;
2-amino-N-ethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
2-amino-N-[2-(dimethylamino)ethyl]-N-methyl-5-[4-(4-pyridinyl)-6-quinolin-
yl]-3-pyridinesulfonamide;
2-amino-N-(3-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridine-
sulfonamide;
2-amino-N-3-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonam-
ide;
2-amino-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonami-
de;
2-amino-N-(3-hydroxypropyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridin-
esulfonamide;
3-(1-piperazinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine-
;
3-{[4-(methylsulfonyl)-1-piperazinyl]sulfonyl}-5-[4-(4-pyridinyl)-6-quin-
olinyl]-2-pyridinamine;
2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-N-[3-(1-pyrrolidinyl)propyl]-3-p-
yridinesulfonamide;
3-[(3-amino-1H-pyrazol-1-yl)sulfonyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2--
pyridinamine;
3-[(4-methyl-1-piperazinyl)sulfonyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2-p-
yridinamine;
2-[4-{2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-1-pi-
perazinyl]ethanol;
2-amino-N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridin-
esulfonamide;
2-amino-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-5-[4-(4-pyridinyl)-6-quinoliny-
l]-3-pyridinesulfonamide;
2-amino-N-2-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonam-
ide;
2-amino-N-4-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulf-
onamide;
3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}-5-[4-(4-pyridinyl)-
-6-quinolinyl]-2-pyridinamine;
2-amino-N-[2-(methyloxy)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridin-
esulfonamide;
N,N-dimethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-
-pyridinamine;
N-methyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyr-
idinamine;
N-ethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolin-
yl]-2-pyridinamine;
N,N-diethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2--
pyridinamine;
6-[6-(ethyloxy)-5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)qui-
noline;
6-[6-(methyloxy)-5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyrid-
inyl)quinoline;
3-methyl-7-[4-(4-pyridinyl)-6-quinolinyl]-2H-1,2,4-benzothiadiazine
1,1-dioxide;
6-[4-(4-pyridinyl)-6-quinolinyl]-3,4-dihydro-1(2H)-isoquinolinone;
4-(4-pyridinyl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline;
6-(1H-indazol-5-yl)-4-(4-pyridinyl)quinoline;
6-[4-(4-pyridinyl)-6-quinolinyl]-1H-indazol-3-amine;
4-(4-pyridinyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)quinoline;
6-(1H-indazol-6-yl)-4-(4-pyridinyl)quinoline;
{3-oxo-6-[4-(4-pyridinyl)-6-quinolinyl]-2,3-dihydro-1H-isoindol-1-yl}acet-
ic acid;
4-(4-pyridinyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)quinoline;
6-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-o-
ne;
6-[4-(4-pyridinyl)-6-quinolinyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one;
6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4-pyridinyl)quinoline;
4-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline;
6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;
6-(1-oxido-3-pyridinyl)-4-(4-pyridinyl)quinoline;
4-(4-pyridinyl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-amine;
6-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(4-pyridinyl)quinoline;
2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3--
yl}propanamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}acetam-
ide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}me-
thanesulfonamide;
2-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyrid-
in-3-yl}acetamide;
6-pyrazolo[1,5-a]pyrimidin-6-yl-4-(4-pyridinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one;
6-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;
6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4-pyridinyl)quinoline;
3-[6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4-quinolinyl]benzenesulfonamide;
7-[4-(4-pyridinyl)-6-quinolinyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;
4-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-o-
ne;
2-amino-N,N-dimethyl-5-[2-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyrid-
inesulfonamide;
2-amino-5-[8-fluoro-4-(4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-3-pyridine-
sulfonamide;
2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridine-
sulfonamide;
2-amino-5-[7-fluoro-4-(4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-3-pyridine-
sulfonamide;
5-[5-fluoro-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[7-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[5-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
4-(4-pyridinyl)-6-[5-(trifluoromethyl)-3-pyridinyl]quinoline;
(4,6-di-4-pyridinylquinoline;
6-(3-pyridinyl)-4-(4-pyridinyl)quinoline;
6-(2-pyridinyl)-4-(4-pyridinyl)quinoline;
6-(2,1,3-benzoxadiazol-5-yl)-4-(4-pyridinyl)quinoline;
6-(2,1,3-benzothiadiazol-5-yl)-4-(4-pyridinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;
2-ethyl-6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-pyrimidinone;
7-[4-(4-pyridinyl)-6-quinolinyl]-2-quinoxalinol;
2-(4-morpholinyl)-7-[4-(4-pyridinyl)-6-quinolinyl]quinoxaline;
4-(4-morpholinyl)-6-[4-(4-pyridinyl)-6-quinolinyl]quinazoline;
1-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;
1-(3-methylphenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazo-
l-3-one;
1-(3-chlorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3-
H-pyrazol-3-one;
1-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;
N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfona-
mide; 6-(1H-indol-5-yl)-4-(4-pyridinyl)quinoline;
6-(1H-indol-6-yl)-4-(4-pyridinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-indol-2-one;
6-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-indol-2-one;
7-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-quinazolinone;
6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-quinazolinone;
6-[4-(4-pyridinyl)-6-quinolinyl]-1,2-benzisothiazol-3(2H)-one
1,1-dioxide;
6-[4-(4-pyridinyl)-6-quinolinyl]-1,8-naphthyridin-2(1H)-one;
6-(1,3-benzoxazol-5-yl)-4-(4-pyridinyl)quinoline;
7-[4-(4-pyridinyl)-6-quinolinyl]-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dio-
ne; 3-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinecarboxamide;
5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine;
4-[4-(4-pyridinyl)-6-quinolinyl]thieno[2,3-c]pyridine-2-carboxamide;
methyl
4-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrrolo[2,3-c]pyridine-2-carbo-
xylate;
4-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrrolo[2,3-c]pyridine-2-carbo-
xamide; 6-(1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline;
6-(1H-imidazo[4,5-c]pyridin-2-yl)-4-(4-pyridinyl)quinoline;
6-(1H-imidazo[4,5-b]pyridin-2-yl)-4-(4-pyridinyl)quinoline;
6-(1H-purin-8-yl)-4-(4-pyridinyl)quinoline;
6-imidazo[1,2-a]pyridin-6-yl-4-(4-pyridinyl)quinoline;
6-imidazo[1,2-a]pyrimidin-6-yl-4-(4-pyridinyl)quinoline;
1-{6-[4-(4-pyridinyl)-6-quinolinyl]imidazo[1,2-a]pyridin-3-yl}-1-propanon-
e; 6-(4-pyridazinyl)-4-(4-pyridinyl)quinoline;
1-{6-[4-(4-pyridinyl)-6-quinolinyl]imidazo[1,2-a]pyridin-3-yl}-1-propanol-
; 4-(1-piperidinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;
4-(4-morpholinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;
4-(4-methyl-1-piperazinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;
4-(4-pyridazinyl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline;
6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(1-piperidinyl)quinoline;
6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-morpholinyl)quinoline;
2-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-N,N-dimethyl-3-pyrid-
inesulfonamide;
2-amino-N,N-dimethyl-5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridine-
sulfonamide;
2-amino-5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-N,N-dimeth-
yl-3-pyridinesulfonamide;
2-amino-N,N-dimethyl-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinesulfona-
mide;
2-amino-N,N-dimethyl-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridine-
sulfonamide;
2-amino-N,N-dimethyl-5-(4-phenyl-6-quinolinyl)-3-pyridinesulfonamide;
2-amino-N,N-dimethyl-5-[4-(1H-pyrazol-3-yl)-6-quinolinyl]-3-pyridinesulfo-
namide;
2-amino-5-[4-(2,6-dimethyl-4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-
-3-pyridinesulfonamide;
2-amino-5-(4-{3-[(aminosulfonyl)methyl]phenyl}-6-quinolinyl)-N,N-dimethyl-
-3-pyridinesulfonamide;
2-amino-5-[4-(3-cyanophenyl)-6-quinolinyl]-N,N-dimethyl-3-pyridinesulfona-
mide;
2-amino-5-{4-[5-(aminosulfonyl)-3-pyridinyl]-6-quinolinyl}-N,N-dimet-
hyl-3-pyridinesulfonamide;
5,5'-(4,6-quinolinediyl)di(3-pyridinesulfonamide);
2-amino-N,N-dimethyl-5-[4-(3-{[(1-methylethyl)amino]sulfonyl}phenyl)-6-qu-
inolinyl]-3-pyridinesulfonamide;
2-amino-N,N-dimethyl-5-(4-{3-[(methylamino)sulfonyl]phenyl}-6-quinolinyl)-
-3-pyridinesulfonamide;
2-amino-N,N-dimethyl-5-{4-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-6-quin-
olinyl}-3-pyridinesulfonamide;
5-[4-(3-cyanophenyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-{4-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-6-quinolinyl}-3-pyridinesul-
fonamide;
5-[4-(2,6-dimethyl-4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonam-
ide; 5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;
5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinesulfonam-
ide;
5-[4-(1-methyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;
5-{4-[2-(4-morpholinylmethyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;
5-{4-[2-(4-morpholinylcarbonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamid-
e;
5-{4-[2-(4-morpholinyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;
4'-(4-pyridinyl)-3,4-dihydro-6,6'-biquinolin-2(1H)-one;
6-[4-(4-pyridinyl)-6-quinolinyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbaldehyde;
{2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methyl
acetate; 5-[4-(4-pyridinyl)-6-quinolinyl]-2,3-pyridinediamine;
2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;
6-[4-(4-pyridinyl)-6-quinolinyl]pyrido[2,3-d]pyrimidin-4(1H)-one;
5-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1,2-dihydro-3H-pyrazol-3-
-one;
7-[4-(4-pyridinyl)-6-quinolinyl]pyrido[3,2-d]pyrimidin-4(1H)-one;
6-[5-(1H-pyrazol-5-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxa-
mide; 6-[2-(methyloxy)-4-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[6-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
4-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinol;
6-[2-(methyloxy)-5-pyrimidinyl]-4-(4-pyridinyl)quinoline;
{6-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}methanol;
6-(2-chloro-4-pyridinyl)-4-(4-pyridinyl)quinoline;
4-(4-pyridinyl)-6-(5-pyrimidinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-2(1H)-pyrimidinone;
6-[2,6-bis(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[6-(4-morpholinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-(6-chloro-3-pyridinyl)-4-(4-pyridinyl)quinoline;
6-[6-(ethyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
N,N-dimethyl-3-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}oxy)-1-propa-
namine; 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;
methyl 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinecarboxylate;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}acetamide;
N-[2-(4-morpholinyl)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamin-
e; 6-[6-(1-piperazinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[5-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-(6-fluoro-3-pyridinyl)-4-(4-pyridinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyrimidinecarbonitrile;
6-[2-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbonitrile;
6-[6-(methyloxy)-2-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[5-(4-morpholinylcarbonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[4-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
7-[4-(4-pyridinyl)-6-quinolinyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine;
5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbaldehyde;
6-(4-chloro-3-pyridinyl)-4-(4-pyridinyl)quinoline;
4-(4-pyridinyl)-6-[5-(1H-tetrazol-5-yl)-3-pyridinyl]quinoline;
N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
N,N-dimethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
6-[4-methyl-6-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
N-{4-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}acetamide;
6-(4-methyl-3-pyridinyl)-4-(4-pyridinyl)quinoline;
6-[5-(1,3,4-oxadiazol-2-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
2-amino-N-(4-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridine-
sulfonamide;
2-amino-N,N-diethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamid-
e;
5-[4-(4-pyridinyl)-6-quinolinyl]-3-(1-pyrrolidinylsulfonyl)-2-pyridinam-
ine;
2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-N-[2-(1-pyrrolidinyl)ethyl]--
3-pyridinesulfonamide;
6-[6-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
2-amino-N-(phenylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfo-
namide;
2-amino-N-(2-hydroxyethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyri-
dinesulfonamide;
1-({2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-4-pipe-
ridinol;
2-amino-N-(2-aminoethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyrid-
inesulfonamide;
6-[5-(methylthio)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
6-[5-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
2-amino-N-(2-hydroxyethyl)-N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-py-
ridinesulfonamide;
2-amino-N-cyclopropyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonam-
ide;
2-amino-N-1,3-benzodioxol-5-yl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyr-
idinesulfonamide;
N,N-diethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
1-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-4-piperidinol;
4-(4-pyridinyl)-6-[5-(1-pyrrolidinylsulfonyl)-3-pyridinyl]quinoline;
N-(2-hydroxyethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide-
;
N-(phenylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
5-[4-(4-pyridinyl)-6-quinolinyl]-N-[2-(1-pyrrolidinyl)ethyl]-3-pyridinesu-
lfonamide;
6-{5-[(4-methyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-4-(4-pyrid-
inyl)quinoline;
N-cyclopropyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
N-[2-(methyloxy)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfona-
mide;
N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
N-1,3-benzodioxol-5-yl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfona-
mide;
N-(3-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesul-
fonamide;
N-2-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfona-
mide;
N-(2-chlorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfon-
amide;
N-cyclohexyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide-
;
N-[2-(methyloxy)phenyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfo-
namide;
2,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benze-
nesulfonamide;
1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazole-4--
sulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiophenesulfonamide;
3,5-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-4-isoxazole-
sulfonamide;
3,4-bis(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzen-
esulfonamide;
2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1-propanesulfon-
amide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropanesulfona-
mide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonami-
de; and
1-phenyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanesu-
lfonamide;
5-{4-[3-chloro-4-(methyloxy)phenyl]-6-quinolinyl}-3-pyridinesul-
fonamide;
5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonami-
de;
5-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-6-quinolinyl}-3-pyridinesulf-
onamide;
N-(cyclopropylsulfonyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyr-
idinyl}cyclopropanesulfonamide;
N-(2,4-difluorophenyl)-5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyr-
idinesulfonamide;
N-methyl-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;
N-(2,4-difluorophenyl)-5-(4-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}--
6-quinolinyl)-3-pyridinesulfonamide;
N-(2,4-difluorophenyl)-5-[4-(4-isoquinolinyl)-6-quinolinyl]-3-pyridinesul-
fonamide;
N-phenyl-N'-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}urea;
2-{4-[6-(5-{[(2,4-difluorophenyl)amino]sulfonyl}-3-pyridinyl)-4-quinoliny-
l]-1H-pyrazol-1-yl}acetamide;
N-{5-[4-(1-methyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}benzenesulfo-
namide; 4'-(4-pyridinyl)-3,6'-biquinoline;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzamide;
5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-N-(2,4-difluorophenyl)-3-pyridines-
ulfonamide;
6-[5-(1H-pyrazol-4-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;
N,N-diethyl-2-oxo-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3-pyridine-
sulfonamide;
4-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamid-
e;
N-methyl-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamid-
e;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}ethanesulfonamide;
4-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulf-
onamide;
4-(1-methylethyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl-
}benzenesulfonamide;
2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine;
4-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonami-
de;
N-{5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}-2,4-diflu-
orobenzenesulfonamide;
1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-H-pyrazole-3-su-
lfonamide;
2-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzen-
esulfonamide;
N-{2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamid-
e;
N-{2-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfona-
mide;
N-{2-cyano-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfo-
namide;
2-methyl-5-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}b-
enzenesulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyrazole-4-sulfonamid-
e;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-methyl-5-ni-
trobenzenesulfonamide;
N-{2-chloro-5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}benz-
enesulfonamide;
N-{2-chloro-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfona-
mide;
3-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}benzenesulfo-
namide;
2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesu-
lfonamide;
2,4-difluoro-N-{5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}-
benzenesulfonamide;
5-fluoro-2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzene-
sulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-nitrobenzenes-
ulfonamide;
N-{2-chloro-5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzene-
sulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-methylbenzene-
sulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-fluorobenzene-
sulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiophenesulf-
onamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopro-
panesulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-5-fluoro-2-meth-
ylbenzenesulfonamide;
N-(2-chloro-5-{4-[3-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl)ben-
zenesulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3,5-dimethyl-4--
isoxazolesulfonamide;
2,4-difluoro-N-(5-{4-[3-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl-
)benzenesulfonamide;
2,4-difluoro-N-{5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinyl}ben-
zenesulfonamide;
3-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulf-
onamide;
N-[4-(cyanomethyl)phenyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyri-
dinesulfonamide;
3-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonami-
de;
N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenes-
ulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2,4-difluoroben-
zenesulfonamide;
3-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamid-
e;
N-{5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-3-pyridinyl}-2,4-difluorobenz-
enesulfonamide;
3-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamid-
e;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-4-(trifluoromethyl)ben-
zenesulfonamide;
N-{2-hydroxy-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonam-
ide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-(trifluoromethyl)b-
enzenesulfonamide;
N-{5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-2-chloro-3-pyridinyl}benzenesul-
fonamide;
N-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzami-
de;
2,4-difluoro-N-{5-[4-(4-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzen-
esulfonamide;
N-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonami-
de;
2,4-difluoro-N-[5-(4-pyrazolo[1,5-a]pyridin-3-yl-6-quinolinyl)-3-pyrid-
inyl]benzenesulfonamide;
2,4-difluoro-N-{5-[4-(2-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzenesu-
lfonamide;
2,4-difluoro-N-(5-{4-[4-(trifluoromethyl)phenyl]-6-quinolinyl}--
3-pyridinyl)benzenesulfonamide;
2,4-difluoro-N-(5-{4-[4-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl-
)benzenesulfonamide; methyl
1-methyl-5-[{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}amino)sulfonyl]-
-1H-pyrrole-2-carboxylate;
5-bromo-2-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}ben-
zenesulfonamide;
5-(5-isoxazolyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiop-
henesulfonamide;
2,4-difluoro-N-{5-[4-(3-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzenesu-
lfonamide;
2,4-difluoro-N-(5-{4-[3-(trifluoromethyl)phenyl]-6-quinolinyl}--
3-pyridinyl)benzenesulfonamide;
2-chloro-4-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenes-
ulfonamide;
N-[5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinyl]-2,-
4-difluorobenzenesulfonamide;
N-[5-(4-{4-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinyl]-2,-
4-difluorobenzenesulfonamide;
1,2-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazol-
e-4-sulfonamide;
3-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinolinyl]b-
enzamide;
4-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-qui-
nolinyl]benzamide;
N-{4-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinoliny-
l]phenyl}acetamide;
N-{3-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinoliny-
l]phenyl}acetamide;
6-(4-morpholinyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-pyri-
dinesulfonamide;
2-fluoro-4-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzene-
sulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-furansulfonamide;
1,3-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyrazole-
-4-sulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-(trifluoromethyl)benze-
nesulfonamide;
N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclohexane-
sulfonamide;
N-[5-(4-cyclopentyl-6-quinolinyl)-2-(methyloxy)-3-pyridinyl]benzenesulfon-
amide;
2,5-dichloro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzen-
esulfonamide;
3-cyano-4-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenes-
ulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1-pyrrolidinesulfonamide-
;
(5Z)-5-({5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methylidene)-1,3-t-
hiazolidine-2,4-dione;
N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropan-
esulfonamide;
N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-pyridinesulfonamide;
1,2-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazol-
e-5-sulfonamide;
1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-(trifluoromet-
hyl)-1H-pyrazole-4-sulfonamide;
1,3,5-trimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyraz-
ole-4-sulfonamide;
N-{2-(ethyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfo-
namide;
N,N-dimethyl-N'-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulf-
amide;
N-{2-chloro-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}-2,4-dif-
luorobenzenesulfonamide;
N-{2-chloro-1-oxido-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenes-
ulfonamide;
N-{6-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonami-
de;
N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanes-
ulfonamide;
N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanesulfonami-
de;
2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyr-
idinyl}benzenesulfonamide; and/or a pharmaceutically acceptable
salt thereof.
This invention also relates to a method of treating cancer, which
comprises co-administering to a subject in need thereof an
effective amount of a compound of Formula (I), and/or a
pharmaceutically acceptable salt thereof, and at least one
anti-neoplastic agent such as one selected from the group
consisting of: anti-microtubule agents, platinum coordination
complexes, alkylating agents, antibiotic agents, topoisomerase II
inhibitors, antimetabolites, topoisomerase I hinibitors, hormones
and hormonal anlogues, signal transduction pathway inhibitors,
non-receptor tyrosine kinase angiogenesis inhibitors,
immunotherapeutic agents, proapoptotic agents, and cell cycle
signaling inhibitors.
This invention also relates to a method of treating cancer, which
comprises co-administering to a subject in need thereof an
effective amount of a compound of Formula (I), and/or a
pharmaceutically acceptable salt thereof; and at least one signal
transduction pathway inhibitor such as one selected from the group
consisting of: receptor tyrosine kinase inhibitor, non-receptor
tyrosine kinase inhibitor, SH2/SH3 domain blocker, serine/threonine
kinase inhibitor, phosphotidyl inositol-3 kinase inhibitor,
myo-inositol singaling inhibitor, and Ras oncogene inhibitor.
As used herein, the term "effective amount" means that amount of a
drug or pharmaceutical agent that will elicit the biological or
medical response of a tissue, system, animal or human that is being
sought, for instance, by a researcher or clinician. Furthermore,
the term "therapeutically effective amount" means any amount which,
as compared to a corresponding subject who has not received such
amount, results in improved treatment, healing, prevention, or
amelioration of a disease, disorder, or side effect, or a decrease
in the rate of advancement of a disease or disorder. The term also
includes within its scope amounts effective to enhance normal
physiological function.
Compounds of Formula (I) are included in the pharmaceutical
compositions of the invention.
DEFINITIONS
By the term "substituted amino" as used herein, is meant --NR30R40
wherein each R30 and R40 is independently selected from a group
including hydrogen, C1-6alkyl, acyl, C3-C7cycloalkyl, wherein at
least one of R30 and R40 is not hydrogen.
By the term "acyl" as used herein, unless otherwise defined, is
meant --C(O)(alkyl), --C(O)(cycloalkyl), --C(O)(aryl) or
--C(O)(heteroaryl), wherein heteroaryl and aryl are optionally
substituted.
By the term "aryl" as used herein, unless otherwise defined, is
meant aromatic, hydrocarbon, ring system. The ring system may be
monocyclic or fused polycyclic (e.g. bicyclic, tricyclic, etc.). In
various embodiments, the monocyclic aryl ring is C5-C10, or C5-C7,
or C5-C6, where these carbon numbers refer to the number of carbon
atoms that form the ring system. A C6 ring system, i.e. a phenyl
ring is a suitable aryl group. In various embodiments, the
polycyclic ring is a bicyclic aryl group, where suitable bicyclic
aryl groups are C8-C12, or C9-C10. A naphthyl ring, which has 10
carbon atoms, is a suitable polycyclic aryl group.
By the term "heteroaryl" as used herein, unless otherwise defined,
is meant an aromatic ring system containing carbon(s) and at least
one heteroatom. Heteroaryl may be monocyclic or polycyclic. A
monocyclic heteroaryl group may have 1 to 4 heteroatoms in the
ring, while a polycyclic heteroaryl may contain 1 to 10 hetero
atoms. A polycyclic heteroaryl ring may contain fused, spiro or
bridged ring junctions, for example, bicyclic heteroaryl is a
polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8
to 12 member atoms. Monocyclic heteroaryl rings may contain from 5
to 8 member atoms (carbons and heteroatoms). Exemplary heteroaryl
groups include but are not limited to: benzofuran, benzothiophene,
furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline,
quinoxaline, thiazole, and thiophene.
By the term "monocyclic heteroaryl" as used herein, unless
otherwise defined, is meant a monocyclic heteroaryl ring containing
1-5 carbon atoms and 1-4 hetero atoms.
By the term "alkylcarboxy" as used herein, unless otherwise
defined, is meant --(CH.sub.2).sub.nCOOR.sub.80, wherein R80 is
hydrogen or C1-C6alkyl, n is 0-6.
By the term "alkoxy" as used herein is meant --O(alkyl) including
--OCH.sub.3, --OCH.sub.2CH.sub.3 and --OC(CH.sub.3).sub.3 where
alkyl is as described herein.
By the term "alkylthio" as used herein is meant --S(alkyl)
including --SCH.sub.3, --SCH.sub.2CH.sub.3 where alkyl is as
described herein.
The term "cycloalkyl" as used herein unless otherwise defined, is
meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic
C3-C12.
Examples of cycloalkyl and substituted cycloalkyl substituents as
used herein include: cyclohexyl, aminocyclohexyl, cyclobutyl,
aminocyclobutyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl,
propyl-4-methoxycyclohexyl, 4-methoxycyclohexyl,
4-carboxycyclohexyl, cyclopropyl, aminocyclopentyl, and
cyclopentyl.
By the term "heterocycloalkyl" as used herein is meant a
non-aromatic, unsaturated or saturated, monocyclic or polycyclic,
heterocyclic ring containing at least one carbon and at least one
heteroatom. Exemplary monocyclic heterocyclic rings include:
piperidine, piperazine, pyrrolidine, and morpholine. Exemplary
polycyclic heterocyclic rings include quinuclidine.
By the term "substituted" as used herein, unless otherwise defined,
is meant that the subject chemical moiety has one to five
substituents, suitably from one to three substituents selected from
the group consisting of: hydrogen, halogen, C1-C6alkyl, amino,
urea, trifluoromethyl, --(CH.sub.2).sub.nCOOH, C3-C7cycloalkyl,
substituted amino, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
heteroarylalkyl, heterocycloalkyl, cyano, hydroxyl, alkoxy,
alkylthio, aryloxy, acyloxy, acyl, acylamino, aminoacyl, arylamino,
nitro, oxo, --CO.sub.2R.sub.50, --SO.sub.2R.sub.70,
--NR.sub.50SO.sub.2R.sub.70, NR.sub.50C(O)R.sub.75 and
--CONR.sub.55R.sub.60, wherein R.sub.50 and R.sub.55 are each
independently selected from: hydrogen, alkyl, and C3-C7cycloalkyl;
R.sub.55 and R.sub.60 can optionally form a heterocycloalkyl ring;
n is 0 to 6; R.sub.75 is selected from the group consisting of:
C1-C6alkyl, C3-7cylcoalkyl, substituted C3-7cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteraryl, amino,
substituted amino, arylamino, C1-C6heterocycloalkyl, alkoxy,
aryloxy and substituted C1-C6heterocycloalkyl; each R60 and R70 is
independently selected from the group consisting of: C1-C6alkyl,
C3-C7cycloalkyl, substituted C1-C6heterocycloalkyl,
C1-C6heterocycloalkyl, halogen, amino, substituted amino,
arylamino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo,
--(CH.sub.2).sub.nCOOH, aryl optionally fused with a five-membered
ring or substituted with one to five groups selected from the group
consisting of: C1-C6alkyl, C3-C7cycloalkyl, halogen, amino,
substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo,
or --(CH.sub.2).sub.nCOOH, or heteroaryl optionally fused with a
five-membered ring or substituted with one to five groups selected
from the group consisting of: C1-C6alkyl, C3-C7cycloalkyl, halogen,
amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or
--(CH.sub.2).sub.nCOOH.
By the term "substituted", when referred in the definition of R60,
R70, R75, "arylamino", and "aryloxy", is meant that the subject
chemical moiety has one to five substituents, suitably from one to
three, selected from the group consisting of: hydrogen, C1-C6alkyl,
halogen, trifluoromethyl, --(CH.sub.2).sub.nCOOH, amino,
substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy,
acyloxy, acyl, acylamino, and nitro, n is 0-6.
By the term "acyloxy" as used herein is meant --OC(O)alkyl where
alkyl is as described herein. Examples of acyloxy substituents as
used herein include: --OC(O)CH.sub.3, --OC(O)CH(CH.sub.3).sub.2 and
--OC(O)(CH.sub.2).sub.3CH.sub.3.
By the term "acylamino" as used herein is meant --N(H)C(O)alkyl,
--N(H)C(O)(cycloalkyl) where alkyl is as described herein. Examples
of N-acylamino substituents as used herein include:
--N(H)C(O)CH.sub.3, --N(H)C(O)CH(CH.sub.3).sub.2 and
--N(H)C(O)(CH.sub.2).sub.3CH.sub.3.
By the term "aminoacyl" as used herein is meant
--C(O)N(alkyl).sub.n, --C(O)N(cycloalkyl).sub.n where alkyl is as
described herein, n is 1-2.
By the term "aryloxy" as used herein is meant --O(aryl),
--O(substituted aryl), --O(heteroaryl) or --O(substituted
heteroaryl).
By the term "arylamino" as used herein is meant --NR.sub.80(aryl),
--NR.sub.80(substituted aryl), --NR.sub.80(heteroaryl) or
--NR.sub.80(substituted heteroaryl), wherein R80 is H, C1-6alkyl or
C3-C7cycloalkyl.
By the term "heteroatom" as used herein is meant oxygen, nitrogen
or sulfur.
By the term "halogen" as used herein is meant a substituent
selected from bromide, iodide, chloride and fluoride.
By the term "alkyl" and derivatives thereof and in all carbon
chains as used herein, including alkyl chains defined by the term
"--(CH.sub.2).sub.n", "--(CH.sub.2).sub.m" and the like, is meant a
linear or branched, saturated or unsaturated hydrocarbon chain, and
unless otherwise defined, the carbon chain will contain from 1 to
12 carbon atoms.
By the term "substituted alkyl" as used herein is meant an alkyl
group substituted with one to six substituents selected from the
group consisting of: halogen, trifluoromethyl, alkylcarboxy, amino,
substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy,
acyloxy, acyl, acylamino, carbamate, urea, sulfonamate,
C3-7cycloheteralkyl, C3-7cycloalkyl and nitro.
Examples of alkyl and substituted alkyl substituents as used herein
include: --CH.sub.3, --CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2--CH.sub.2--C(CH.sub.3).sub.3, --CH.sub.2--CF.sub.3,
--C.ident.C--C(CH.sub.3).sub.3, --C.ident.C--CH.sub.2--OH,
cyclopropylmethyl,
--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--NH.sub.2,
--C.ident.C--C.sub.6H.sub.5, --C.ident.C--C(CH.sub.3).sub.2--OH,
--CH.sub.2--CH(OH)--CH(OH)--CH(OH)--CH(OH)--CH.sub.2--OH,
piperidinylmethyl, methoxyphenylethyl, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.3--CH.sub.3, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, --CH.dbd.CH.sub.2, and
--C.ident.C--CH.sub.3.
By the term "treating" and derivatives thereof as used herein, is
meant prophylatic and therapeutic therapy. Prophylatic therapy is
meant the institution of measures to protect a person from a
disease to which he or she has been, or may be, exposed. Also
called preventive treatment.
By the term "co-administering" and derivatives thereof as used
herein is meant either simultaneous administration or any manner of
separate sequential administration of a PI3 kinase inhibiting
compound, as described herein, and a further active ingredient or
ingredients. The term further active ingredient or ingredients, as
used herein, includes any compound or therapeutic agent known to or
that demonstrates advantageous properties when administered to a
patient in need of treatment. Suitably, if the administration is
not simultaneous, the compounds are administered in a close time
proximity to each other. Furthermore, it does not matter if the
compounds are administered in the same dosage form, e.g. one
compound may be administered topically and another compound may be
administered orally.
The term "compound" as used herein includes all isomers of the
compound. Examples of such isomers include: enantiomers, tautomers,
rotamers.
In formula (V) to (X), when a "dot" bond is drawn between two
atoms, it is meant that such bond can be either single or double
bond. A ring system containing such bonds can be aromatic or
non-aromatic.
Certain compounds described herein may contain one or more chiral
atoms, or may otherwise be capable of existing as two enantiomers,
or two or more diastereoisomers. Accordingly, the compounds of this
invention include mixtures of enantiomers/diastereoisomers as well
as purified enantiomers/diastereoisomers or
enantiomerically/diastereoisomerically enriched mixtures. Also
included within the scope of the invention are the individual
isomers of the compounds represented by formula I or II above as
well as any wholly or partially equilibrated mixtures thereof. The
present invention also covers the individual isomers of the
compounds represented by the formulas above as mixtures with
isomers thereof in which one or more chiral centers are inverted.
Further, an example of a possible tautomer is an oxo substituent in
place of a hydroxy substituent. Also, as stated above, it is
understood that all tautomers and mixtures of tautomers are
included within the scope of the compounds of Formula I or II.
Compounds of Formula (I) are included in the pharmaceutical
compositions of the invention. Where a --COOH or --OH group is
present, pharmaceutically acceptable esters can be employed, for
example methyl, ethyl, pivaloyloxymethyl, and the like for --COOH,
and acetate maleate and the like for --OH, and those esters known
in the art for modifying solubility or hydrolysis characteristics,
for use as sustained release or prodrug formulations.
It has now been found that compounds of the present invention are
inhibitors of the Phosphatoinositides 3-kinases (PI3Ks),
particularly PI3K.alpha.. When the phosphatoinositides 3-kinase
(PI3K) enzyme is inhibited by a compound of the present invention,
PI3K is unable to exert its enzymatic, biological and/or
pharmacological effects. The compounds of the present invention are
therefore useful in the treatment of autoimmune disorders,
inflammatory diseases, cardiovascular diseases, neurodegenerative
diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney
diseases, platelet aggregation, cancer, sperm motility,
transplantation rejection, graft rejection and lung injuries,
particularly cancer.
Compounds according to Formula (I) are suitable for the modulation,
notably the inhibition of the activity of phosphatoinositide
3-kinases (PI3K), suitably phosphatoinositides 3-kinase
(PI3K.alpha.). Therefore the compounds of the present invention are
also useful for the treatment of disorders which are mediated by
PI3Ks. Said treatment involves the modulation--notably the
inhibition or the down regulation--of the phosphatoinositides
3-kinases.
Suitably, the compounds of the present invention are used for the
preparation of a medicament for the treatment of a disorder
selected from multiple sclerosis, psoriasis, rheumatoid arthritis,
systemic lupus erythematosis, inflammatory bowel disease, lung
inflammation, thrombosis or brain infection/inflammation, such as
meningitis or encephalitis, Alzheimer's disease, Huntington's
disease, CNS trauma, stroke or ischemic conditions, cardiovascular
diseases such as athero-sclerosis, heart hypertrophy, cardiac
myocyte dysfunction, elevated blood pressure or
vasoconstriction.
Suitably, the compounds of Formula (I) are useful for the treatment
of autoimmune diseases or inflammatory diseases such as multiple
sclerosis, psoriasis, rheumatoid arthritis, systemic lupus
erythematosis, inflammatory bowel disease, lung inflammation,
thrombosis or brain infection/inflammation such as meningitis or
encephalitis.
Suitably, the compounds of Formula (I) are useful for the treatment
of neurodegenerative diseases including multiple sclerosis,
Alzheimer's disease, Huntington's disease, CNS trauma, stroke or
ischemic conditions.
Suitably, the compounds of Formula (I) are useful for the treatment
of cardiovascular diseases such as atherosclerosis, heart
hypertrophy, cardiac myocyte dysfunction, elevated blood pressure
or vasoconstriction.
Suitably, the compounds of Formula (I) are useful for the treatment
of chronic obstructive pulmonary disease, anaphylactic shock
fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemic
conditions, ischemia-reperfusion, platelets aggregation/activation,
skeletal muscle atrophy/hypertrophy, leukocyte recruitment in
cancer tissue, angiogenesis, invasion metastasis, in particular
melanoma, Karposi's sarcoma, acute and chronic bacterial and virual
infections, sepsis, transplantation rejection, graft rejection,
glomerulo sclerosis, glomerulo nephritis, progressive renal
fibrosis, endothelial and epithelial injuries in the lung, and lung
airway inflammation.
Because the pharmaceutically active compounds of the present
invention are active as PI3 kinase inhibitors, particularly the
compounds that inhibit PI3K.alpha., either selectively or in
conjunction with one or more of PI3K.delta., PI3K.beta., and/or
PI3K.gamma., they exhibit therapeutic utility in treating
cancer.
Suitably, the invention relates to a method of treating cancer in a
mammal, including a human, wherein the cancer is selected from:
brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana
syndrome, Cowden disease, Lhermitte-Duclos disease, breast,
inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,
Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and
neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate,
sarcoma, osteosarcoma, giant cell tumor of bone and thyroid.
Suitably, the invention relates to a method of treating cancer in a
mammal, including a human, wherein the cancer is selected from:
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia,
Chronic lymphocytic leukemia, Hairy-cell leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia, Chronic
neutrophilic leukemia, Acute lymphoblastic T cell leukemia,
Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell
leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple
myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia and
Erythroleukemia.
Suitably, the invention relates to a method of treating cancer in a
mammal, including a human, wherein the cancer is selected from:
malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,
lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular
lymphoma.
Suitably, the invention relates to a method of treating cancer in a
mammal, including a human, wherein the cancer is selected from:
neuroblastoma, bladder cancer, urothelial cancer, lung cancer,
vulval cancer, cervical cancer, endometrial cancer, renal cancer,
mesothelioma, esophageal cancer, salivary gland cancer,
hepatocellular cancer, gastric cancer, nasopharangeal cancer,
buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal
tumor) and testicular cancer.
When a compound of Formula (I) is administered for the treatment of
cancer, the term "co-administering" and derivatives thereof as used
herein is meant either simultaneous administration or any manner of
separate sequential administration of a PI3 kinase inhibiting
compound, as described herein, and a further active ingredient or
ingredients, known to be useful in the treatment of cancer,
including chemotherapy and radiation treatment. The term further
active ingredient or ingredients, as used herein, includes any
compound or therapeutic agent known to or that demonstrates
advantageous properties when administered to a patient in need of
treatment for cancer. Preferably, if the administration is not
simultaneous, the compounds are administered in a close time
proximity to each other. Furthermore, it does not matter if the
compounds are administered in the same dosage form, e.g. one
compound may be administered topically and another compound may be
administered orally.
Typically, any anti-neoplastic agent that has activity versus a
susceptible tumor being treated may be co-administered in the
treatment of cancer in the present invention. Examples of such
agents can be found in Cancer Principles and Practice of Oncology
by V. T. Devita and S. Hellman (editors), 6.sup.th edition (Feb.
15, 2001), Lippincott Williams & Wilkins Publishers. A person
of ordinary skill in the art would be able to discern which
combinations of agents would be useful based on the particular
characteristics of the drugs and the cancer involved. Typical
anti-neoplastic agents useful in the present invention include, but
are not limited to, anti-microtubule agents such as diterpenoids
and vinca alkaloids; platinum coordination complexes; alkylating
agents such as nitrogen mustards, oxazaphosphorines,
alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents
such as anthracyclins, actinomycins and bleomycins; topoisomerase
II inhibitors such as epipodophyllotoxins; antimetabolites such as
purine and pyrimidine analogues and anti-folate compounds;
topoisomerase I inhibitors such as camptothecins; hormones and
hormonal analogues; signal transduction pathway inhibitors;
non-receptor tyrosine kinase angiogenesis inhibitors;
immunotherapeutic agents; proapoptotic agents; and cell cycle
signaling inhibitors.
Examples of a further active ingredient or ingredients
(anti-neoplastic agent) for use in combination or co-administered
with the presently invented AKT inhibiting compounds are
chemotherapeutic agents.
Anti-microtubule or anti-mitotic agents are phase specific agents
active against the microtubules of tumor cells during M or the
mitosis phase of the cell cycle. Examples of anti-microtubule
agents include, but are not limited to, diterpenoids and vinca
alkaloids.
Diterpenoids, which are derived from natural sources, are phase
specific anti-cancer agents that operate at the G.sub.2/M phases of
the cell cycle. It is believed that the diterpenoids stabilize the
.beta.-tubulin subunit of the microtubules, by binding with this
protein. Disassembly of the protein appears then to be inhibited
with mitosis being arrested and cell death following. Examples of
diterpenoids include, but are not limited to, paclitaxel and its
analog docetaxel.
Paclitaxel,
5.beta.,20-epoxy-1,2.alpha.1,4,7.beta.,10,13.alpha.-hexa-hydroxytax-11-en-
-9-one 4,10-diacetate 2-benzoate 13-ester with
(2R,3S)--N-benzoyl-3-phenylisoserine; is a natural diterpene
product isolated from the Pacific yew tree Taxus brevifolia and is
commercially available as an injectable solution TAXOL.RTM.. It is
a member of the taxane family of terpenes. It was first isolated in
1971 by Wani et al. J. Am. Chem., Soc., 93:2325. 1971), who
characterized its structure by chemical and X-ray crystallographic
methods. One mechanism for its activity relates to paclitaxel's
capacity to bind tubulin, thereby inhibiting cancer cell growth.
Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980);
Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem,
256: 10435-10441 (1981). For a review of synthesis and anticancer
activity of some paclitaxel derivatives see: D. G. I. Kingston et
al., Studies in Organic Chemistry vol. 26, entitled "New trends in
Natural Products Chemistry 1986", Attaur-Rahman, P. W. Le Quesne,
Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
Paclitaxel has been approved for clinical use in the treatment of
refractory ovarian cancer in the United States (Markman et al.,
Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al.,
Ann. Intem, Med., 111:273, 1989) and for the treatment of breast
cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is
a potential candidate for treatment of neoplasms in the skin
(Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and
neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The
compound also shows potential for the treatment of polycystic
kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer
and malaria. Treatment of patients with paclitaxel results in bone
marrow suppression (multiple cell lineages, Ignoff, R. J. et. al,
Cancer Chemotherapy Pocket Guides 1998) related to the duration of
dosing above a threshold concentration (50 nM) (Kearns, C. M. et.
al., Seminars in Oncology, 3(6) p. 16-23, 1995).
Docetaxel, (2R,3S)--N-carboxy-3-phenylisoserine, N-tert-butyl
ester, 13-ester with
5.beta.-20-epoxy-1,2.alpha.,4,7.beta.,10.beta.,
13.alpha.-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate,
trihydrate; is commercially available as an injectable solution as
TAXOTERE.RTM.. Docetaxel is indicated for the treatment of breast
cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v.,
prepared using a natural precursor, 10-deacetyl-baccatin III,
extracted from the needle of the European Yew tree. The dose
limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived
from the periwinkle plant. Vinca alkaloids act at the M phase
(mitosis) of the cell cycle by binding specifically to tubulin.
Consequently, the bound tubulin molecule is unable to polymerize
into microtubules. Mitosis is believed to be arrested in metaphase
with cell death following. Examples of vinca alkaloids include, but
are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available
as VELBAN.RTM. as an injectable solution. Although, it has possible
indication as a second line therapy of various solid tumors, it is
primarily indicated in the treatment of testicular cancer and
various lymphomas including Hodgkin's Disease; and lymphocytic and
histiocytic lymphomas. Myelosuppression is the dose limiting side
effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially
available as ONCOVIN.RTM. as an injectable solution. Vincristine is
indicated for the treatment of acute leukemias and has also found
use in treatment regimens for Hodgkin's and non-Hodgkin's malignant
lymphomas. Alopecia and neurologic effects are the most common side
effect of vincristine and to a lesser extent myelosupression and
gastrointestinal mucositis effects occur.
Vinorelbine, 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine
[R--(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commercially
available as an injectable solution of vinorelbine tartrate
(NAVELBINE.RTM.), is a semisynthetic vinca alkaloid. Vinorelbine is
indicated as a single agent or in combination with other
chemotherapeutic agents, such as cisplatin, in the treatment of
various solid tumors, particularly non-small cell lung, advanced
breast, and hormone refractory prostate cancers. Myelosuppression
is the most common dose limiting side effect of vinorelbine.
Platinum coordination complexes are non-phase specific anti-cancer
agents, which are interactive with DNA. The platinum complexes
enter tumor cells, undergo, aquation and form intra- and
interstrand crosslinks with DNA causing adverse biological effects
to the tumor. Examples of platinum coordination complexes include,
but are not limited to, cisplatin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available
as PLATINOL.RTM. as an injectable solution. Cisplatin is primarily
indicated in the treatment of metastatic testicular and ovarian
cancer and advanced bladder cancer. The primary dose limiting side
effects of cisplatin are nephrotoxicity, which may be controlled by
hydration and diuresis, and ototoxicity.
Carboplatin, platinum, diammine
[1,1-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available
as PARAPLATIN.RTM. as an injectable solution. Carboplatin is
primarily indicated in the first and second line treatment of
advanced ovarian carcinoma. Bone marrow suppression is the dose
limiting toxicity of carboplatin.
Alkylating agents are non-phase anti-cancer specific agents and
strong electrophiles. Typically, alkylating agents form covalent
linkages, by alkylation, to DNA through nucleophilic moieties of
the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl,
carboxyl, and imidazole groups. Such alkylation disrupts nucleic
acid function leading to cell death. Examples of alkylating agents
include, but are not limited to, nitrogen mustards such as
cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates
such as busulfan; nitrosoureas such as carmustine; and triazenes
such as dacarbazine.
Cyclophosphamide,
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine
2-oxide monohydrate, is commercially available as an injectable
solution or tablets as CYTOXAN.RTM.. Cyclophosphamide is indicated
as a single agent or in combination with other chemotherapeutic
agents, in the treatment of malignant lymphomas, multiple myeloma,
and leukemias. Alopecia, nausea, vomiting and leukopenia are the
most common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is
commercially available as an injectable solution or tablets as
ALKERAN.RTM.. Melphalan is indicated for the palliative treatment
of multiple myeloma and non-resectable epithelial carcinoma of the
ovary. Bone marrow suppression is the most common dose limiting
side effect of melphalan.
Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is
commercially available as LEUKERAN.RTM. tablets. Chlorambucil is
indicated for the palliative treatment of chronic lymphatic
leukemia, and malignant lymphomas such as lymphosarcoma, giant
follicular lymphoma, and Hodgkin's disease. Bone marrow suppression
is the most common dose limiting side effect of chlorambucil.
Busulfan, 1,4-butanediol dimethanesulfonate, is commercially
available as MYLERAN.RTM. TABLETS. Busulfan is indicated for the
palliative treatment of chronic myelogenous leukemia. Bone marrow
suppression is the most common dose limiting side effects of
busulfan.
Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially
available as single vials of lyophilized material as BiCNU.RTM..
Carmustine is indicated for the palliative treatment as a single
agent or in combination with other agents for brain tumors,
multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas.
Delayed myelosuppression is the most common dose limiting side
effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide,
is commercially available as single vials of material as
DTIC-Dome.RTM.. Dacarbazine is indicated for the treatment of
metastatic malignant melanoma and in combination with other agents
for the second line treatment of Hodgkin's Disease. Nausea,
vomiting, and anorexia are the most common dose limiting side
effects of dacarbazine.
Antibiotic anti-neoplastics are non-phase specific agents, which
bind or intercalate with DNA. Typically, such action results in
stable DNA complexes or strand breakage, which disrupts ordinary
function of the nucleic acids leading to cell death. Examples of
antibiotic anti-neoplastic agents include, but are not limited to,
actinomycins such as dactinomycin, anthrocyclins such as
daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available
in injectable form as COSMEGEN.RTM.. Dactinomycin is indicated for
the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea,
vomiting, and anorexia are the most common dose limiting side
effects of dactinomycin.
Daunorubicin,
(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranos-
yl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5, 12
naphthacenedione hydrochloride, is commercially available as a
liposomal injectable form as DAUNOXOME.RTM. or as an injectable as
CERUBIDINE.RTM.. Daunorubicin is indicated for remission induction
in the treatment of acute nonlymphocytic leukemia and advanced HIV
associated Kaposi's sarcoma. Myelosuppression is the most common
dose limiting side effect of daunorubicin.
Doxorubicin,
(8S,10S)-10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranosyl)oxy]-8--
glycoloyl, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12
naphthacenedione hydrochloride, is commercially available as an
injectable form as RUBEX.RTM. or ADRIAMYCIN RDF.RTM.. Doxorubicin
is primarily indicated for the treatment of acute lymphoblastic
leukemia and acute myeloblastic leukemia, but is also a useful
component in the treatment of some solid tumors and lymphomas.
Myelosuppression is the most common dose limiting side effect of
doxorubicin.
Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated
from a strain of Streptomyces verticillus, is commercially
available as BLENOXANE.RTM.. Bleomycin is indicated as a palliative
treatment, as a single agent or in combination with other agents,
of squamous cell carcinoma, lymphomas, and testicular carcinomas.
Pulmonary and cutaneous toxicities are the most common dose
limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to,
epipodophyllotoxins.
Epipodophyllotoxins are phase specific anti-neoplastic agents
derived from the mandrake plant. Epipodophyllotoxins typically
affect cells in the S and G.sub.2 phases of the cell cycle by
forming a ternary complex with topoisomerase II and DNA causing DNA
strand breaks. The strand breaks accumulate and cell death follows.
Examples of epipodophyllotoxins include, but are not limited to,
etoposide and teniposide.
Etoposide, 4'-demethyl-epipodophyllotoxin
9[4,6-0-(R)-ethylidene-.beta.-D-glucopyranoside], is commercially
available as an injectable solution or capsules as VePESID.RTM. and
is commonly known as VP-16. Etoposide is indicated as a single
agent or in combination with other chemotherapy agents in the
treatment of testicular and non-small cell lung cancers.
Myelosuppression is the most common side effect of etoposide. The
incidence of leucopenia tends to be more severe than
thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin
9[4,6-0-(R)-thenylidene-.beta.-D-glucopyranoside], is commercially
available as an injectable solution as VUMON.RTM. and is commonly
known as VM-26. Teniposide is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
acute leukemia in children. Myelosuppression is the most common
dose limiting side effect of teniposide. Teniposide can induce both
leucopenia and thrombocytopenia.
Antimetabolite neoplastic agents are phase specific anti-neoplastic
agents that act at S phase (DNA synthesis) of the cell cycle by
inhibiting DNA synthesis or by inhibiting purine or pyrimidine base
synthesis and thereby limiting DNA synthesis. Consequently, S phase
does not proceed and cell death follows. Examples of antimetabolite
anti-neoplastic agents include, but are not limited to,
fluorouracil, methotrexate, cytarabine, mercaptopurine,
thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is
commercially available as fluorouracil. Administration of
5-fluorouracil leads to inhibition of thymidylate synthesis and is
also incorporated into both RNA and DNA. The result typically is
cell death. 5-fluorouracil is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
carcinomas of the breast, colon, rectum, stomach and pancreas.
Myelosuppression and mucositis are dose limiting side effects of
5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro
deoxyuridine (floxuridine) and 5-fluorodeoxyuridine
monophosphate.
Cytarabine, 4-amino-1-.beta.-D-arabinofuranosyl-2(1H)-pyrimidinone,
is commercially available as CYTOSAR-U.RTM. and is commonly known
as Ara-C. It is believed that cytarabine exhibits cell phase
specificity at S-phase by inhibiting DNA chain elongation by
terminal incorporation of cytarabine into the growing DNA chain.
Cytarabine is indicated as a single agent or in combination with
other chemotherapy agents in the treatment of acute leukemia. Other
cytidine analogs include 5-azacytidine and
2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces
leucopenia, thrombocytopenia, and mucositis.
Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is
commercially available as PURINETHOL.RTM.. Mercaptopurine exhibits
cell phase specificity at S-phase by inhibiting DNA synthesis by an
as of yet unspecified mechanism. Mercaptopurine is indicated as a
single agent or in combination with other chemotherapy agents in
the treatment of acute leukemia. Myelosuppression and
gastrointestinal mucositis are expected side effects of
mercaptopurine at high doses. A useful mercaptopurine analog is
azathioprine.
Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is
commercially available as TABLOID.RTM.. Thioguanine exhibits cell
phase specificity at S-phase by inhibiting DNA synthesis by an as
of yet unspecified mechanism. Thioguanine is indicated as a single
agent or in combination with other chemotherapy agents in the
treatment of acute leukemia. Myelosuppression, including
leucopenia, thrombocytopenia, and anemia, is the most common dose
limiting side effect of thioguanine administration. However,
gastrointestinal side effects occur and can be dose limiting. Other
purine analogs include pentostatin, erythrohydroxynonyladenine,
fludarabine phosphate, and cladribine.
Gemcitabine, 2'-deoxy-2',2'-difluorocytidine monohydrochloride
(.beta.-isomer), is commercially available as GEMZAR.RTM..
Gemcitabine exhibits cell phase specificity at S-phase and by
blocking progression of cells through the G1/S boundary.
Gemcitabine is indicated in combination with cisplatin in the
treatment of locally advanced non-small cell lung cancer and alone
in the treatment of locally advanced pancreatic cancer.
Myelosuppression, including leucopenia, thrombocytopenia, and
anemia, is the most common dose limiting side effect of gemcitabine
administration.
Methotrexate,
N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic
acid, is commercially available as methotrexate sodium.
Methotrexate exhibits cell phase effects specifically at S-phase by
inhibiting DNA synthesis, repair and/or replication through the
inhibition of dyhydrofolic acid reductase which is required for
synthesis of purine nucleotides and thymidylate. Methotrexate is
indicated as a single agent or in combination with other
chemotherapy agents in the treatment of choriocarcinoma, meningeal
leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast,
head, neck, ovary and bladder. Myelosuppression (leucopenia,
thrombocytopenia, and anemia) and mucositis are expected side
effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives
are available or under development as Topoisomerase I inhibitors.
Camptothecins cytotoxic activity is believed to be related to its
Topoisomerase I inhibitory activity. Examples of camptothecins
include, but are not limited to irinotecan, topotecan, and the
various optical forms of
7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptoth-
ecin described below.
Irinotecan HCl,
(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)
carbonyloxy]-1H-pyrano[3',4',6,7]indolizino[1,2-b]quinoline-3,14(4H,
12H)-dione hydrochloride, is commercially available as the
injectable solution CAMPTOSAR.RTM..
Irinotecan is a derivative of camptothecin which binds, along with
its active metabolite SN-38, to the topoisomerase I--DNA complex.
It is believed that cytotoxicity occurs as a result of irreparable
double strand breaks caused by interaction of the topoisomerase
I:DNA:irintecan or SN-38 ternary complex with replication enzymes.
Irinotecan is indicated for treatment of metastatic cancer of the
colon or rectum. The dose limiting side effects of irinotecan HCl
are myelosuppression, including neutropenia, and GI effects,
including diarrhea.
Topotecan HCl,
(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]-
indolizino[1,2-b]quinoline-3,14-(4H, 12H)-dione monohydrochloride,
is commercially available as the injectable solution HYCAMTIN.RTM..
Topotecan is a derivative of camptothecin which binds to the
topoisomerase I--DNA complex and prevents religation of singles
strand breaks caused by Topoisomerase I in response to torsional
strain of the DNA molecule. Topotecan is indicated for second line
treatment of metastatic carcinoma of the ovary and small cell lung
cancer. The dose limiting side effect of topotecan HCl is
myelosuppression, primarily neutropenia.
Also of interest, is the camptothecin derivative of formula A
following, currently under development, including the racemic
mixture (R,S) form as well as the R and S enantiomers:
##STR00019## known by the chemical name
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptotheci-
n (racemic mixture) or
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin
(R enantiomer) or
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin
(S enantiomer). Such compound as well as related compounds are
described, including methods of making, in U.S. Pat. Nos.
6,063,923; 5,342,947; 5,559,235; 5,491,237 and pending U.S. patent
application Ser. No. 08/977,217 filed Nov. 24, 1997.
Hormones and hormonal analogues are useful compounds for treating
cancers in which there is a relationship between the hormone(s) and
growth and/or lack of growth of the cancer. Examples of hormones
and hormonal analogues useful in cancer treatment include, but are
not limited to, adrenocorticosteroids such as prednisone and
prednisolone which are useful in the treatment of malignant
lymphoma and acute leukemia in children; aminoglutethimide and
other aromatase inhibitors such as anastrozole, letrazole,
vorazole, and exemestane useful in the treatment of adrenocortical
carcinoma and hormone dependent breast carcinoma containing
estrogen receptors; progestrins such as megestrol acetate useful in
the treatment of hormone dependent breast cancer and endometrial
carcinoma; estrogens, androgens, and anti-androgens such as
flutamide, nilutamide, bicalutamide, cyproterone acetate and
5.alpha.-reductases such as finasteride and dutasteride, useful in
the treatment of prostatic carcinoma and benign prostatic
hypertrophy; anti-estrogens such as tamoxifen, toremifene,
raloxifene, droloxifene, iodoxyfene, as well as selective estrogen
receptor modulators (SERMS) such those described in U.S. Pat. Nos.
5,681,835, 5,877,219, and 6,207,716, useful in the treatment of
hormone dependent breast carcinoma and other susceptible cancers;
and gonadotropin-releasing hormone (GnRH) and analogues thereof
which stimulate the release of leutinizing hormone (LH) and/or
follicle stimulating hormone (FSH) for the treatment prostatic
carcinoma, for instance, LHRH agonists and antagagonists such as
goserelin acetate and luprolide.
Signal transduction pathway inhibitors are those inhibitors, which
block or inhibit a chemical process which evokes an intracellular
change. As used herein this change is cell proliferation or
differentiation. Signal tranduction inhibitors useful in the
present invention include inhibitors of receptor tyrosine kinases,
non-receptor tyrosine kinases, SH2/SH3domain blockers,
serine/threonine kinases, phosphotidyl inositol-3 kinases,
myo-inositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of
specific tyrosyl residues in various proteins involved in the
regulation of cell growth. Such protein tyrosine kinases can be
broadly classified as receptor or non-receptor kinases.
Receptor tyrosine kinases are transmembrane proteins having an
extracellular ligand binding domain, a transmembrane domain, and a
tyrosine kinase domain. Receptor tyrosine kinases are involved in
the regulation of cell growth and are generally termed growth
factor receptors. Inappropriate or uncontrolled activation of many
of these kinases, i.e. aberrant kinase growth factor receptor
activity, for example by over-expression or mutation, has been
shown to result in uncontrolled cell growth. Accordingly, the
aberrant activity of such kinases has been linked to malignant
tissue growth. Consequently, inhibitors of such kinases could
provide cancer treatment methods. Growth factor receptors include,
for example, epidermal growth factor receptor (EGFr), platelet
derived growth factor receptor (PDGFr), erbB2, erbB4, vascular
endothelial growth factor receptor (VEGFr), tyrosine kinase with
immunoglobulin-like and epidermal growth factor homology domains
(TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony
stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth
factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC),
ephrin (eph) receptors, and the RET protooncogene. Several
inhibitors of growth receptors are under development and include
ligand antagonists, antibodies, tyrosine kinase inhibitors and
anti-sense oligonucleotides. Growth factor receptors and agents
that inhibit growth factor receptor function are described, for
instance, in Kath, John C., Exp. Opin. Ther. Patents (2000)
10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997; and Lofts,
F. J. et al, "Growth factor receptors as targets", New Molecular
Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David,
CRC press 1994, London.
Tyrosine kinases, which are not growth factor receptor kinases are
termed non-receptor tyrosine kinases. Non-receptor tyrosine kinases
for use in the present invention, which are targets or potential
targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak,
cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and
Bcr-Abl. Such non-receptor kinases and agents which inhibit
non-receptor tyrosine kinase function are described in Sinh, S, and
Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell
Research 8 (5): 465-80; and Bolen, J. B., Brugge, J. S., (1997)
Annual review of Immunology. 15: 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain
binding in a variety of enzymes or adaptor proteins including,
PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk,
Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer
drugs are discussed in Smithgall, T. E. (1995), Journal of
Pharmacological and Toxicological Methods. 34(3) 125-32.
Inhibitors of Serine/Threonine Kinases including MAP kinase cascade
blockers which include blockers of Raf kinases (rafk), Mitogen or
Extracellular Regulated Kinase (MEKs), and Extracellular Regulated
Kinases (ERKs); and Protein kinase C family member blockers
including blockers of PKCs (alpha, beta, gamma, epsilon, mu,
lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family
kinases, akt kinase family members, and TGF beta receptor kinases.
Such Serine/Threonine kinases and inhibitors thereof are described
in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of
Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R.
(2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J.,
Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P. A., and
Harris, A. L. (1995), Cancer Treatment and Research. 78: 3-27,
Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10),
2000, 223-226; U.S. Pat. No. 6,268,391; and Martinez-Iacaci, L., et
al, Int. J. Cancer (2000), 88(1), 44-52.
Inhibitors of Phosphotidyl inositol-3 Kinase family members
including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be
useful in the present invention. Such kinases are discussed in
Abraham, R. T. (1996), Current Opinion in Immunology. 8 (3) 412-8;
Canman, C. E., Lim, D. S. (1998), Oncogene 17 (25) 3301-3308;
Jackson, S. P. (1997), International Journal of Biochemistry and
Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000)
60(6), 1541-1545.
Also of interest in the present invention are Myo-inositol
signaling inhibitors such as phospholipase C blockers and
Myoinositol analogues. Such signal inhibitors are described in
Powis, G., and Kozikowski A., (1994) New Molecular Targets for
Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press
1994, London.
Another group of signal transduction pathway inhibitors are
inhibitors of Ras Oncogene. Such inhibitors include inhibitors of
farnesyltransferase, geranyl-geranyl transferase, and CAAX
proteases as well as anti-sense oligonucleotides, ribozymes and
immunotherapy. Such inhibitors have been shown to block ras
activation in cells containing wild type mutant ras, thereby acting
as antiproliferation agents. Ras oncogene inhibition is discussed
in Scharovsky, O. G., Rozados, V. R., Gervasoni, S. I. Matar, P.
(2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M. N.
(1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim.
Biophys. Acta, (19899) 1423(3):19-30.
As mentioned above, antibody antagonists to receptor kinase ligand
binding may also serve as signal transduction inhibitors. This
group of signal transduction pathway inhibitors includes the use of
humanized antibodies to the extracellular ligand binding domain of
receptor tyrosine kinases. For example Imclone C225 EGFR specific
antibody (see Green, M. C. et al, Monoclonal Antibody Therapy for
Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286);
Herceptin.RTM. erbB2 antibody (see Tyrosine Kinase Signalling in
Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast cancer
Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see
Brekken, R. A. et al, Selective Inhibition of VEGFR2Activity by a
monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer
Res. (2000) 60, 5117-5124).
Non-receptor kinase angiogenesis inhibitors may also be useful in
the present invention. Inhibitors of angiogenesis related VEGFR and
TIE2 are discussed above in regard to signal transduction
inhibitors (both receptors are receptor tyrosine kinases).
Angiogenesis in general is linked to erbB2/EGFR signaling since
inhibitors of erbB2 and EGFR have been shown to inhibit
angiogenesis, primarily VEGF expression. Accordingly, non-receptor
tyrosine kinase inhibitors may be used in combination with the
compounds of the present invention. For example, anti-VEGF
antibodies, which do not recognize VEGFR (the receptor tyrosine
kinase), but bind to the ligand; small molecule inhibitors of
integrin (alpha.sub.v beta.sub.3) that will inhibit angiogenesis;
endostatin and angiostatin (non-RTK) may also prove useful in
combination with the disclosed compounds. (See Bruns C J et al
(2000), Cancer Res., 60: 2926-2935; Schreiber A B, Winkler M E, and
Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000),
Oncogene 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in
combination with the compounds of formula (I). There are a number
of immunologic strategies to generate an immune response. These
strategies are generally in the realm of tumor vaccinations. The
efficacy of immunologic approaches may be greatly enhanced through
combined inhibition of signaling pathways using a small molecule
inhibitor. Discussion of the immunologic/tumor vaccine approach
against erbB2/EGFR are found in Reilly R T et al. (2000), Cancer
Res. 60: 3569-3576; and Chen Y, Hu D, Eling D J, Robbins J, and
Kipps T J. (1998), Cancer Res. 58: 1965-1971.
Agents used in proapoptotic regimens (e.g., bcl-2 antisense
oligonucleotides) may also be used in the combination of the
present invention. Members of the Bcl-2 family of proteins block
apoptosis. Upregulation of bcl-2 has therefore been linked to
chemoresistance. Studies have shown that the epidermal growth
factor (EGF) stimulates anti-apoptotic members of the bcl-2 family
(i.e., mcl-1). Therefore, strategies designed to downregulate the
expression of bcl-2 in tumors have demonstrated clinical benefit
and are now in Phase II/III trials, namely Genta's G3139 bcl-2
antisense oligonucleotide. Such proapoptotic strategies using the
antisense oligonucleotide strategy for bcl-2 are discussed in Water
J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et
al. (1994), Antisense Res. Dev. 4: 71-79.
Cell cycle signalling inhibitors inhibit molecules involved in the
control of the cell cycle. A family of protein kinases called
cyclin dependent kinases (CDKs) and their interaction with a family
of proteins termed cyclins controls progression through the
eukaryotic cell cycle. The coordinate activation and inactivation
of different cyclin/CDK complexes is necessary for normal
progression through the cell cycle. Several inhibitors of cell
cycle signalling are under development. For instance, examples of
cyclin dependent kinases, including CDK2, CDK4, and CDK6 and
inhibitors for the same are described in, for instance, Rosania et
al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
In one embodiment, the cancer treatment method of the claimed
invention includes the co-administration a compound of formula I
and/or a pharmaceutically acceptable salt thereof and at least one
anti-neoplastic agent, such as one selected from the group
consisting of anti-microtubule agents, platinum coordination
complexes, alkylating agents, antibiotic agents, topoisomerase II
inhibitors, antimetabolites, topoisomerase I inhibitors, hormones
and hormonal analogues, signal transduction pathway inhibitors,
non-receptor tyrosine kinase angiogenesis inhibitors,
immunotherapeutic agents, proapoptotic agents, and cell cycle
signaling inhibitors.
Because the pharmaceutically active compounds of the present
invention are active as PI3 kinase inhibitors, particularly the
compounds that modulate/inhibit PI3K.alpha., it is useful in
treating cancer. Because the pharmaceutically active compounds of
the present invention are also active against one or more of
PI3K.delta., PI3K.beta., and/or PI3K.gamma., they exhibit
therapeutic utility in treating a disease state selected from:
autoimmune disorders, inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, allergy, asthma,
pancreatitis, multiorgan failure, kidney diseases, platelet
aggregation, sperm motility, transplantation rejection, graft
rejection and lung injuries.
When a compound of Formula (I) is administered for the treatment of
a disease state selected from: autoimmune disorders, inflammatory
diseases, cardiovascular diseases, neurodegenerative diseases,
allergy, cancer, asthma, pancreatitis, multiorgan failure, kidney
diseases, platelet aggregation, sperm motility, transplantation
rejection, graft rejection or lung injuries, the term
"co-administering" and derivatives thereof as used herein is meant
either simultaneous administration or any manner of separate
sequential administration of a PI3 kinase inhibiting compound, as
described herein, and a further active ingredient or ingredients,
known to be useful in the treatment of such autoimmune disorder,
cancer, inflammatory diseases, cardiovascular disease,
neurodegenerative disease, allergy, asthma, pancreatitis,
multiorgan failure, kidney diseases, platelet aggregation, sperm
motility, transplantation rejection, graft rejection and/or lung
injuries.
Biological Assays
PI3K alpha Leadseeker SPA Assay
Compounds of the present invention were tested according to the
following assays and found as inhibitors of PI3 kinases,
particularly PI3K.alpha.. The exemplified compounds were tested and
found active against PI3K.alpha.. The IC.sub.50's ranged from about
1 nM to 10 .mu.M. The majority of the compounds were under 500 nM;
the most active compounds were under 10 nM.
The compound of Example 249 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 1.6 nM against PI3K.alpha..
The compound of Example 252 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 0.8 nM against PI3K.alpha..
The compound of Example 263 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 7.9 nM against PI3K.alpha..
The compound of Example 289 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 2.5 nM against PI3K.alpha..
The compound of Example 154 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 316 nM against PI3K.alpha..
The compound of Example 156 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 79 nM against PI3K.alpha..
The compound of Example 224 was tested generally according to the
assays described herein and in at least one experimental run
exhibited a IC50 value: equal to 1000 nM against PI3K.alpha..
Assay Principle
SPA imaging beads are microspheres containing scintillant which
emit light in the red region of the visible spectrum. As a result,
these beads are ideally suited to use with a CCD imager such as the
Viewlux. The Leadseeker beads used in this system are polystyrene
beads that have been coupled with polyethyleneimine. When added to
the assay mixture, the beads absorb both the substrate (PIP2) and
product (PIP3). Adsorbed P.sup.33-PIP3 will cause an increase in
signal, measured as ADUs (analog to digital units). This protocol
details the use of the PEI-PS Leadseeker beads for assays using
His-p110/p85 PI3K alpha.
Assay Protocol
Solid compounds are typically plated with 0.1 .mu.l of 100% DMSO in
all wells (except column 6 and 18) of a 384-well, flat bottom, low
volume plate (Greiner 784075). The compounds are serially diluted
(3-fold in 100% DMSO) across the plate from column 1 to column 12
and column 13 to column 24 and leave column 6 and 18 containing
only DMSO to yield 11 concentrations for each test compound. The
assay buffer contains MOPS (pH 6.5), CHAPS, and DTT. PI3K alpha and
PIP2 (L-alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate
[PI(4,5)P2]3-O-phospho linked, D(+)-sn-1,2-di-O-octanoylglyceryl,
CellSignals #901) are mixed and incubated in the plate with
compound for 30 min prior to starting the reaction with the
addition of P.sup.33-ATP and MgCl.sub.2 (reagents added using
Zoom). Enzyme-free wells (column 18) are typically done to
determine the low control. PEI-PS Leadseeker beads in
PBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and
the plates are allowed to incubate for at least one hour (typically
overnight) before centrifugation. The signal is determined using a
Viewlux detector and is then imported into curve fitting software
(Activity Base) for construction of concentration response curves.
The percent inhibition of activity is calculated relative to high
controls (C1, 0. 1 .mu.l DMSO in column 6, rows A-P)) and low
controls (C2, 5 .mu.l of 40 uM PIP2 in buffer in column 18, rows
A-P) using, 100*(1-(U1-C2)/(C1-C2)). The concentration of test
compound yielding 50% inhibition is determined using the equation,
y=((Vmax*x)/(K+x))+Y2, where "K" is equal to the IC50. The IC50
values are converted to pIC50 values, i.e., -log IC50 in Molar
concentration.
Celluar Assays:
Day 1 Plate cells before noon 10K cells/well in clear flat-bottomed
96-well plates (fv. 105 ul) Last four wells in last column receive
media only Place in 37 degC incubator overnight Compound plate
Prepare in polypropylene round-bottomed 96-well plates; 8 compounds
per plate, 11-pt titrations of each (3.times. serial dilution),
DMSO in last column (0.15% f.c. on cells) 15 ul in first well, 10
ul DMSO in the rest; take 5 ul from first well and mix in next,
continue across plate (excluding last column); seal with foil lid
and place at 4 degC.
Day 2 Take out Lysis buffer inhibitors (4-degC/-20 degC) and
compound plates (4 degC), thaw on bench top; make 1.times. Tris
wash buffer (WB) to fill reservoir on plate washer and top off
bench supply (use MiliQ), turn on centrifuge to allow it to cool
Block MSD plates Make 20 ml 3% blocking solution/plate (600 mg
blocker A in 20 ml WB), add 150 ul/well and incubate at RT for at
least 1 hr Add compound (while blocking) Add 300 ul growth media
(RPMI w/Q, 10% FBS) per well (682.times. dil of compound) to each
compound plate Add 5 ul compound dilution into each well (f.v. 110
ul) on duplicate plates Place in 37 degC incubator for 30 min Make
lysates Prepare MSD Lysis buffer; for 10 ml add 200 ul protease
inhibitor solution, and 100 ul each of Phosphatase inhibitors I
& II (Keep on ice until ready for use) Remove plates
post-incubation, aspirate media with plate washer, wash 1.times.
with cold PBS, and add 80 ul MSD Lysis buffer per well; incubate on
shaker at 4 degC for .gtoreq.30 min Spin cold at 2500 rpm for 10
min; leave plates in 4 degC centrifuge until ready for use AKT
duplex assay Wash plates (4.times. with 200 ul/well WB in plate
washer); tap plates on paper towel to blot Add 60 ul of
lysates/well, incubate on shaker at RT for 1 hr During incubation
prepare detection Ab (3 ml/plate; 2 ml WB and 1 ml blocking
solution w/Ab at 10 nM); repeat wash step as above Add 25 ul of
Ab/well, incubate on shaker at RT for 1 hr; repeat wash step as
above Add 150 ul/well 1.times. Read Buffer (dilute 4.times. stock
in ddH2O, 20 ml/plate), read immediately Analysis Observe all the
data points at each compound concentration. The data point from
highest inhibitor concentration must be equal or greater than 70%
of DMSO control. IC50 for duplicate runs must be within 2-fold of
each other (not flagged in summary template). Y min must be greater
than zero; if both mins are red flagged (>35) then compound is
listed as inactive (IC50=>highest dose). If only one min is red
flagged, but still .ltoreq.50 then call IC50 as listed. Any data
points equal or greater than 30% off the curve will not be
considered. Cell Growth/Death Assay:
BT474, HCC1954 and T-47D (human breast) were cultured in RPMI-1640
containing 10% fetal bovine serum at 37.degree. C. in 5% CO.sub.2
incubator. Cells were split into T75 flask (Falcon #353136) two to
three days prior to assay set up at density which yields
approximately 70-80% confluence at time of harvest for assay. Cells
were harvested using 0.25% trypsin-EDTA (Sigma #4049). Cell counts
were performed on cell suspension using Trypan Blue exclusion
staining. Cells were then plated in 384 well black flat bottom
polystyrene (Greiner #781086) in 48 .mu.l of culture media per well
at 1,000 cells/well. All plates were placed at 5% CO.sub.2,
37.degree. C. overnight and test compounds were added the following
day. One plate was treated with CellTiter-Glo (Promega #G7573) for
a day 0 (t=0) measurement and read as described below. The test
compounds were prepared in clear bottom polypropylene 384 well
plates (Greiner#781280) with consecutive two fold dilutions. 4
.mu.l of these dilutions were added to 105 .mu.l culture media,
after mixing the solution, 2 .mu.l of these dilutions were added
into each well of the cell plates. The final concentration of DMSO
in all wells was 0.15%. Cells were incubated at 37.degree. C., 5%
CO.sub.2 for 72 hours. Following 72 hours of incubation with
compounds each plate was developed and read. CellTiter-Glo reagent
was added to assay plates using a volume equivalent to the cell
culture volume in the wells. Plates were shaken for approximately
two minutes and incubated at room temperature for approximately 30
minutes and chemiluminescent signal was read on the Analyst GT
(Molecular Devices) reader. Results were expressed as a percent of
the t=0 and plotted against the compound concentration. Cell growth
inhibition was determined for each compound by fitting the dose
response with a 4 or 6 parameter curve fit using XLfit software and
determining the concentration that inhibited 50% of the cell growth
(gIC50) with the Y min as the t=0 and Y max as the DMSO control.
Value from wells with no cells was subtracted from all samples for
background correction.
ADDITIONAL REFERENCES
The compounds of the present invention can also be tested to
determine their inhibitory activity at PI3K.alpha., PI3K.delta.,
PI3K.beta. and PI3K.gamma. according to the assays in the following
references:
For all PI3K isoforms: 1. Cloning, expression, purification, and
characterization of the human Class Ia phosphoinositide 3-kinase
isoforms: Meier, T. I.; Cook, J. A.; Thomas, J. E.; Radding, J. A.;
Horn, C.; Lingaraj, T.; Smith, M. C. Protein Expr. Purif., 2004,
35(2), 218. 2. Competitive fluorescence polarization assays for the
detection of phosphoinositide kinase and phosphatase activity:
Drees, B. E.; Weipert, A.; Hudson, H.; Ferguson, C. G.;
Chakravarty, L.; Prestwich, G. D. Comb. Chem. High Throughput
Screen., 2003, 6(4), 321. For PI3K.gamma.: WO 2005/011686 A1
The pharmaceutically active compounds within the scope of this
invention are useful as PI3 Kinase inhibitors in mammals,
particularly humans, in need thereof.
The present invention therefore provides a method of treating
diseases associated with PI3 kinase inhibition, particularly:
autoimmune disorders, inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, allergy, asthma,
pancreatitis, multiorgan failure, kidney diseases, platelet
aggregation, cancer, sperm motility, transplantation rejection,
graft rejection and lung injuries and other conditions requiring
PI3 kinase modulation/inhibition, which comprises administering an
effective compound of Formula (I) or a pharmaceutically acceptable
salt thereof. The compounds of Formula (I) also provide for a
method of treating the above indicated disease states because of
their ability to act as PI3 inhibitors. The drug may be
administered to a patient in need thereof by any conventional route
of administration, including, but not limited to, intravenous,
intramuscular, oral, subcutaneous, intradermal, and parenteral.
The pharmaceutically active compounds of the present invention are
incorporated into convenient dosage forms such as capsules,
tablets, or injectable preparations. Solid or liquid pharmaceutical
carriers are employed. Solid carriers include, starch, lactose,
calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin,
agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid
carriers include syrup, peanut oil, olive oil, saline, and water.
Similarly, the carrier or diluent may include any prolonged release
material, such as glyceryl monostearate or glyceryl distearate,
alone or with a wax. The amount of solid carrier varies widely but,
preferably, will be from about 25 mg to about 1 g per dosage unit.
When a liquid carrier is used, the preparation will be in the form
of a syrup, elixir, emulsion, soft gelatin capsule, sterile
injectable liquid such as an ampoule, or an aqueous or nonaqueous
liquid suspension.
The pharmaceutical preparations are made following conventional
techniques of a pharmaceutical chemist involving mixing,
granulating, and compressing, when necessary, for tablet forms, or
mixing, filling and dissolving the ingredients, as appropriate, to
give the desired oral or parenteral products.
Doses of the presently invented pharmaceutically active compounds
in a pharmaceutical dosage unit as described above will be an
efficacious, nontoxic quantity preferably selected from the range
of 0.001-100 mg/kg of active compound, preferably 0.001-50 mg/kg.
When treating a human patient in need of a PI3K inhibitor, the
selected dose is administered preferably from 1-6 times daily,
orally or parenterally. Preferred forms of parenteral
administration include topically, rectally, transdermally, by
injection and continuously by infusion. Oral dosage units for human
administration preferably contain from 0.05 to 3500 mg of active
compound. Oral administration, which uses lower dosages is
preferred. Parenteral administration, at high dosages, however,
also can be used when safe and convenient for the patient.
Optimal dosages to be administered may be readily determined by
those skilled in the art, and will vary with the particular PI3
kinase inhibitor in use, the strength of the preparation, the mode
of administration, and the advancement of the disease condition.
Additional factors depending on the particular patient being
treated will result in a need to adjust dosages, including patient
age, weight, diet, and time of administration.
The method of this invention of inducing PI3 kinase inhibitory
activity in mammals, including humans, comprises administering to a
subject in need of such activity an effective PI3 kinase
modulating/inhibiting amount of a pharmaceutically active compound
of the present invention.
The invention also provides for the use of a compound of Formula
(I) in the manufacture of a medicament for use as a PI3 kinase
inhibitor.
The invention also provides for the use of a compound of Formula
(I) in the manufacture of a medicament for use in therapy.
The invention also provides for the use of a compound of Formula
(I) in the manufacture of a medicament for use in treating
autoimmune disorders, inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, allergy, asthma,
pancreatitis, multiorgan failure, kidney diseases, platelet
aggregation, cancer, sperm motility, transplantation rejection,
graft rejection and lung injuries.
The invention also provides for a pharmaceutical composition for
use as a PI3 inhibitor which comprises a compound of Formula (I) or
a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for
use in the treatment of autoimmune disorders, inflammatory
diseases, cardiovascular diseases, neurodegenerative diseases,
allergy, asthma, pancreatitis, multiorgan failure, kidney diseases,
platelet aggregation, cancer, sperm motility, transplantation
rejection, graft rejection and lung injuries, which comprises a
compound of Formula (I) or a pharmaceutically acceptable
carrier.
In addition, the pharmaceutically active compounds of the present
invention can be co-administered with further active ingredients,
including compounds known to have utility when used in combination
with a PI3 kinase inhibitor.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent.
The following examples are, therefore, to be construed as merely
illustrative and not a limitation of the scope of the present
invention in any way.
Experimental Details
The compounds of the following examples are readily made according
to Schemes 1 or by analogous methods.
##STR00020## Conditions: a) 2 M HCl in diethylether, THF, rt; then
sodium iodide, propionitrile, reflux; b) aryl (R1) bromide,
palladium catalyst, 2 M K.sub.2CO.sub.3, dioxane, heat; c)
bis(pinacolato)diboron, potassium acetate, palladium catalyst,
dioxane, heat; d) heteroaryl (R2) bromide, palladium catalyst,
saturated aqueous NaHCO.sub.3, dioxane, heat.
Example 1
5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide
##STR00021##
a) 6-bromo-4-iodoquinoline
Following the general procedure of Wolf, Christian et al. (SynLett
2003 12, 1801-1804), to a solution of 6-bromo-4-chloroquinoline (30
g, 0.124 mol) in anhydrous THF (500 mL) was added 2 M HCl in
diethylether (74 mL, 0.148 mol). A white precipitate formed
immediately. After stirring for 30 min, the suspension was
concentrated in vacuo and dried under vacuum to provide
6-bromo-4-chloroquinoline hydrochloride as an off-white solid (34.6
g, quantitative yield).
A 3-neck roundbottom flask equipped with a reflux condenser and
mechanical stirrer was charged with 6-bromo-4-chloroquinoline
hydrochloride (34.6 g, 0.124 mol), anhydrous sodium iodide (92.93
g, 0.62 mol) and propionitrile (1 L). The resulting slurry was
stirred vigorously at reflux for 96 hrs. The solution was cooled to
room temperature and 500 mL of 10% K.sub.2CO.sub.3 solution was
added, followed by a 200 mL of a 5% sodium sulfite solution. The
reaction mixture was extracted with CH.sub.2Cl.sub.2 (600
mL.times.4). The combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and conc. in vacuo to provide the
title compound as an off-white solid (41.8 g, >quantitative
yield), which was used without further purification. LCMS
[.alpha.].sup.+=333.8, 334.8, 336.0 and 337.0; H.sup.1 NMR (400
MHz, d-DMSO) .delta. (ppm)=7.98-7.96 (2H, m), 8.14-8.16 (1H, m),
8.23 (1H, d), 8.53 (1H, d).
b) 6-bromo-4-(4-pyridinyl)quinoline
A 1 L sealed tube charged with 6-bromo-4-iodoquinoline (11.58 g,
0.0347 mol), 4-pyridineboronic acid (5.97 g, 0.0486 mol),
tetrakis(triphenyphosphine)palladium[0] (2.0 g, 0.00173 mol), 2 M
aqueous potassium carbonate (152 mL) and 1,4-dioxane (152 mL) was
stirred at 100.degree. C. for 28 hrs. After cooling to rt, the
organic layer was separated and the aqueous portion extracted with
EtOAc (200 mL.times.3). The combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and partially concentrated in vacuo.
The resultant mixture was filtered to give the title compound (9.13
g) as a tan solid. The residual supernatant was concentrated to
dryness and purified by silica gel chromatography (100% ethyl
acetate to 2% methanol in ethyl acetate) to provide an additional
0.036 g of the title compound as a tan solid (combined 9.166 g, 92%
yield).
LCMS [.alpha.].sup.+=285.9; 287.8. H.sup.1 NMR (400 MHz, d-DMSO)
.delta. (ppm)=7.53-7.71 (3H, m), 7.85 (1H, s), 8.05 (1H, d), 8.17
(1H, d), 8.81 (2H, d), 9.05 (1H, d)
c)
4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-
e
A mixture of (6-bromo-4-(4-pyridinyl)quinoline (5.0 g, 17.5 mmol),
bis(pinacolato)diboron (4.9 g, 19.3 mmole), potassium acetate (5.2
g, 52.6 mmol), and
dichloro-[1,1'bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (430 mg, 0.53 mmol) in dioxane (30 mL) was
heated at 130.degree. C. for 4 h and cooled to room temperature.
The reaction was cooled and filtered through Na.sub.2SO.sub.4 and
Celite onto silica. The mixture was purified by silica gel
chromatography eluting with EtOAc/ethanol (0-20% methanol gradient)
to give the title compound as a semi-pure solid. (2.14 g, 64%) mix
of boronic acid and ester used without further purification.
d) 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide
A mixture of
4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
(250 mg, 0.75 mmol), 5-bromopyridine-3-sulfonamide (213 mg, 0.9
mmol), tetrakistriphenylphosphine palladium (0) (95 mg, 0.08 mmol),
and saturated aqueous NaHCO.sub.3 (2.5 mL), and dioxane (5 mL)) was
heated at 120.degree. C. for 1 h and cooled to room temperature.
The reaction mixture was filtered through Celite and the solvent
was removed under reduced pressure. The crude product was purified
by Gilson reverse phase HPLC (8-25% 6 min gradient 0.1% TFA in
H.sub.2O/CH.sub.3CN) followed by neutralization with saturated
aqueous NaHCO.sub.3 and extracted into EtOAc. Evaporation provided
the title compound as an off white solid. (85 mg, 31%). ESMS
[M+H].sup.+=363.1
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 1:
TABLE-US-00001 MS(ES) Example Structure [M + H].sup.+ 2
##STR00022## 338 3 ##STR00023## 411 4 ##STR00024## 448 5
##STR00025## 392 6 ##STR00026## 406 7 ##STR00027## 378 8
##STR00028## 367 9 ##STR00029## 338 10 ##STR00030## 338 11
##STR00031## 436 12 ##STR00032## 447 13 ##STR00033## 525 14
##STR00034## 489 15 ##STR00035## 444 16 ##STR00036## 461 17
##STR00037## 491 18 ##STR00038## 490 19 ##STR00039## 503 20
##STR00040## 454 21 ##STR00041## 454 22 ##STR00042## 557 23
##STR00043## 436 24 ##STR00044## 476 25 ##STR00045## 462 26
##STR00046## 476 27 ##STR00047## 504 28 ##STR00048## 477 29
##STR00049## 463 30 ##STR00050## 396 31 ##STR00051## 340 32
##STR00052## 341 33 ##STR00053## 324 34 ##STR00054## 324 35
##STR00055## 300 36 ##STR00056## 323 37 ##STR00057## 339 38
##STR00058## 339 39 ##STR00059## 409 40 ##STR00060## 417 41
##STR00061## 411 42 ##STR00062## 324 43 ##STR00063## 340 44
##STR00064## 337 45 ##STR00065## 355 46 ##STR00066## 339 47
##STR00067## 352 48 ##STR00068## 284 49 ##STR00069## 325 50
##STR00070## 341 51 ##STR00071## 351 52 ##STR00072## 420 53
##STR00073## 420 59 ##STR00074## 475 60 ##STR00075## 324 61
##STR00076## 407 62 ##STR00077## 395 63 ##STR00078## 395 64
##STR00079## 498 65 ##STR00080## 485 66 ##STR00081## 364 67
##STR00082## 352 68 ##STR00083## 366 69 ##STR00084## 300 70
##STR00085## 313 71 ##STR00086## 433 72 ##STR00087## 341 73
##STR00088## 363 74 ##STR00089## 341 75 ##STR00090## 352 76
##STR00091## 377 77 ##STR00092## 391 78 ##STR00093## 328 79
##STR00094## 355 80 ##STR00095## 352 81 ##STR00096## 469 82
##STR00097## 475 83 ##STR00098## 362 84 ##STR00099## 468 85
##STR00100## 422 86 ##STR00101## 462 87 ##STR00102## 421 88
##STR00103## 436 89 ##STR00104## 418 90 ##STR00105## 498 91
##STR00106## 419 92 ##STR00107## 447 93 ##STR00108## 417 94
##STR00109## 407 95 ##STR00110## 453 96 ##STR00111## 460 97
##STR00112## 446 98 ##STR00113## 403 99 ##STR00114## 421 100
##STR00115## 439 101 ##STR00116## 483 102 ##STR00117## 453 103
##STR00118## 440 104 ##STR00119## 473.2 105 ##STR00120## 445.3 106
##STR00121## 469.1 249 ##STR00122## 489.1 250 ##STR00123## 453.0
251 ##STR00124## 532 252 ##STR00125## 487.1 253 ##STR00126## 478.9
254 ##STR00127## 505.1 255 ##STR00128## 492.1 256 ##STR00129##
411.1 257 ##STR00130## 426 258 ##STR00131## 441 259 ##STR00132##
396 260 ##STR00133## 492 261 ##STR00134## 535 262 ##STR00135## 525
263 ##STR00136## 521 264 ##STR00137## 492 265 ##STR00138## 490 266
##STR00139## 487 267 ##STR00140## 507 268 ##STR00141## 453 269
##STR00142## 442 270 ##STR00143## 464 271 ##STR00144## 391
272 ##STR00145## 468 273 ##STR00146## 481 274 ##STR00147## 484 275
##STR00148## 478 276 ##STR00149## 418 277 ##STR00150## 491 278
##STR00151## 437
##STR00152## Conditions: a) heteroaryl (R2) boronic acid or
heteroaryl (R2) boronate, palladium catalyst, 2 M potassium
carbonate, heat; or heteroaryl (R2) stannane, palladium catalyst,
dioxane, heat.
Example 107
6-[5-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline
##STR00153##
A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol),
5-methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol),
tetrakistriphenylphosphine palladium (0) (104 mg, 0.09 mmol), and
sat. aqueous NaHCO.sub.3 (1.75 mL), in dioxane (5 mL) was heated at
110.degree. C. for 1 h then cooled to room temperature. The
r.times.n was filtered through Celite and Na.sub.2SO.sub.4 onto
silica and the crude product was purified by column chromatography
(5% EtOAc/Hex--10% Ethanol/EtOAc; 30 min gradient). Evaporation and
precipitation from MeOH/water (2/98) provided the title compound as
a yellow solid. (160 mg, 50%). ESMS [M+H].sup.+=362.1
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 107:
TABLE-US-00002 MS(ES) Example Structure [M + H].sup.+ 108
##STR00154## 323 109 ##STR00155## 284 110 ##STR00156## 284 111
##STR00157## 285 112 ##STR00158## 527 113 ##STR00159## 391 114
##STR00160## 313 115 ##STR00161## 313 116 ##STR00162## 314 117
##STR00163## 317 118 ##STR00164## 285 119 ##STR00165## 301 120
##STR00166## 344 121 ##STR00167## 382 122 ##STR00168## 369 123
##STR00169## 318 124 ##STR00170## 328 125 ##STR00171## 385 126
##STR00172## 412 127 ##STR00173## 368 128 ##STR00174## 313 129
##STR00175## 302 130 ##STR00176## 310 131 ##STR00177## 313 132
##STR00178## 309 133 ##STR00179## 313 134 ##STR00180## 397 135
##STR00181## 3130 136 ##STR00182## 317 137 ##STR00183## 298 138
##STR00184## 330 139 ##STR00185## 362 279 ##STR00186## 334.1
##STR00187## Conditions: a) aryl (R1) boronic acid or aryl (R1)
boronate, palladium catalyst, 2 M potassium carbonate, dioxane,
heat; then heteroaryl (R2) boronic acid or heteroaryl (R2)
boronate, palladium catalyst, 2 M potassium carbonate, heat.
Example 139
2-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide
##STR00188##
A mixture of 4-iodo-6-bromoquinoline (1.18 g, 3.53 mmol),
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
(1 g, 3.53 mmol), dichloro-[1,1'bis(diphenylphosphino)
ferrocene]palladium (II) dichloromethane adduct (177 mg, 0.176
mmol), 2 M potassium carbonate (5 mL), in dioxane (15 mL) was
heated at 100.degree. C. for 1.5 h and cooled to room temperature.
LCMS indicated the reaction was finished. To the finished reaction
was added
2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinesulfona-
mide (1.2 g, 4 mmol), Dichloro-[1,1'bis(diphenylphosphino)
ferrocene]Palladium (II) dichloromethane adduct (177 mg, 0.176
mmol), and 2 M potassium carbonate (5 mL). The reaction was heated
at 100.degree. C. for 3 h and cooled to room temperature. The
dioxane and water were separated and the dioxane evaporated to get
the crude product which was purified on silica gel eluting with
ethyl acetate/methanol, 0-3% methanol. The product which
crystallized from ethyl acetate contained ethyl acetate. The ethyl
acetate was removed by dissolving the product in a excess of
acetone and evaporation. Residual acetone was then removed by
triturating with distilled water at 60 deg followed by filtration
and drying under vacuum. A yield of the title compound (540 mg,
31%) was obtained. MS(ES)+ m/e 484 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 139
TABLE-US-00003 Ex- MS(ES) am- [M + ple Structure H].sup.+ 140
##STR00189## 442 141 ##STR00190## 527 142 ##STR00191## 498 143
##STR00192## 504 144 ##STR00193## 387 145 ##STR00194## 377 146
##STR00195## 461 147 ##STR00196## 391 148 ##STR00197## 461 149
##STR00198## 475 150 ##STR00199## 442 151 ##STR00200## 341 152
##STR00201## 341
##STR00202## Conditions: a) aryl (R1) boronic acid or aryl (R1)
boronate, palladium catalyst, 2 M potassium carbonate, dioxane,
heat; b) bis(pinacolato)diboron, potassium acetate, palladium
catalyst, dioxane, heat; then heteroaryl (R2) bromide, palladium
catalyst, 2 M potassium carbonate, heat.
Example 153
2-amino-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide
##STR00203##
a) 6-bromo-4-(1H-pyrazol-4-yl)quinoline
A mixture of 6-bromo-4-iodoquinoline (1.37 g, 4 mmol) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (852
mg, 4 mmol), dichloro-[1,1'bis(diphenylphosphino)
ferrocene]palladium (II) dichloromethane adduct (162 mg, 0.2 mmol),
2 M potassium carbonate (6 mL), in dioxane (25 mL) was heated at
100.degree. C. for 1.5 h and cooled to room temperature. The
dioxane and water were separated and the dioxane evaporated to get
the crude product which was purified on silica gel eluting with
ethyl acetate/methanol, 0-3% methanol. A yield of the title
compound (340 mg, 34%) was obtained. MS(ES)+ m/e 275
[M+H].sup.+.
b)
2-amino-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide
6-bromo-4-(1H-pyrazol-4-yl)quinoline (330 mg, 1.2 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (304 mg,
1.2 mmol), dichloro-[1,1'bis(diphenylphosphino)ferrocene]palladium
(II) dichloromethane adduct (48 mg, 0.06 mmol), potassium acetate
(352 mg, 3.6 mmol), in dioxane (5 mL) was heated at 100.degree. C.
for 1.5 h and cooled to room temperature. LCMS indicated the
reaction was complete (formation of
4-(1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinol-
ine).
To this same reaction mixture was added
dichloro-[1,1'bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (48 mg, 0.06 mmol),
2-amino-5-bromo-3-pyridinesulfonamide (280 mg, 1 mmol) and 2 M
potassium carbonate (1.5 mL). The reaction mixture was heated a
second time to 115.degree. C. for 18 h. The dioxane and water were
separated and the dioxane evaporated. The crude product was
trituated with methylene chloride (insoluble), then dissolved in
DMF and filtered through a glass fiber filter. The DMF was
evaporated and the product triturated with methanol, filtered and
dried. A yield of the title compound (108 mg, 22%, two steps) was
obtained. MS(ES)+ m/e 395 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 153
TABLE-US-00004 MS(ES) Example Structure [M + H].sup.+ 154
##STR00204## 401 155 ##STR00205## 352 156 ##STR00206## 323 157
##STR00207## 338 158 ##STR00208## 323 159 ##STR00209## 323 160
##STR00210## 338 161 ##STR00211## 402 162 ##STR00212## 322 163
##STR00213## 322 164 ##STR00214## 338 165 ##STR00215## 338 166
##STR00216## 351 167 ##STR00217## 351 168 ##STR00218## 388 169
##STR00219## 351 170 ##STR00220## 324 171 ##STR00221## 368 172
##STR00222## 342 173 ##STR00223## 299 174 ##STR00224## 383 175
##STR00225## 381 176 ##STR00226## 366 177 ##STR00227## 434 178
##STR00228## 352 179 ##STR00229## 353 180 ##STR00230## 327 181
##STR00231## 357 182 ##STR00232## 314 183 ##STR00233## 341 184
##STR00234## 352 185 ##STR00235## 352 186 ##STR00236## 350 187
##STR00237## 439 188 ##STR00238## 473 280 ##STR00239## 411 281
##STR00240## 407.2 282 ##STR00241## 349.7 283 ##STR00242## 416.9
284 ##STR00243## 332.7 285 ##STR00244## 469.1 286 ##STR00245##
417.3 287 ##STR00246## 453.0 288 ##STR00247## 475.1 289
##STR00248## 460.2 290 ##STR00249## 432.2 291 ##STR00250## 435.2
292 ##STR00251## 509.1 293 ##STR00252## 513
##STR00253## Conditions: a) bis(pinacolato)diboron, p palladium
catalyst, potassium acetate, dioxane, heat; then heteroaryl (R2)
bromide, palladium catalyst, 2 M potassium carbonate, heat; then
aryl (R1) boronic acid or aryl (R1) boronate, palladium catalyst, 2
M potassium carbonate, heat.
Example 189
2-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide
##STR00254##
This compound was prepared in one pot (three steps) with no workups
between steps. A mixture of 6-bromo-4-chloroquinoline, (484 mg, 2
mmol), bis(pinacolato)diboron, (506 mg, 2 mmol),
dichloro-[1,1'bis(diphenylphosphino) ferrocene]palladium (II)
dichloromethane adduct (81.5 mg, 0.1 mmol), and potassium acetate
(588 mg, 6 mmol) in dioxane (6 mL) was heated at 100.degree. C. for
4 h. To this reaction was added
2-amino-5-bromo-3-pyridinesulfonamide, (560 mg 2 mmol) an equal
amount of the palladium catalyst used above (0.1 mmol) and 2 M
potassium carbonate (3 mL). The reaction was heated at 95 deg
centigrade for one hour. To this reaction was added
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide,
(566 mg 2 mmol), dichloro-[1,1'bis(diphenylphosphino)
ferrocene]palladium (II) dichloromethane adduct (81.5 mg, 0.1 mmol)
and 2 M potassium carbonate (3 mL). The reaction was heated at
95.degree. C. for three hours. The solvent was evaporated and the
crude material purified by silica gel chromatography, eluting with
ethyl acetate. The product was purified further by crystallizing
from hot ethyl acetate. Obtained 181 mg (18.7%) for three steps.
MS(ES)+ m/e 484 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 189:
TABLE-US-00005 MS(ES) Ex- [M + ample Structure H].sup.+ 190
##STR00255## 420 191 ##STR00256## 484 192 ##STR00257## 420 193
##STR00258## 572 194 ##STR00259## 405 195 ##STR00260## 420 196
##STR00261## 469 294 ##STR00262## 514 295 ##STR00263## 489 296
##STR00264## 514 297 ##STR00265## 492 298 ##STR00266## 514 299
##STR00267## 492 300 ##STR00268## 542 301 ##STR00269## 552 302
##STR00270## 492 303 ##STR00271## 542 304 ##STR00272## 581 305
##STR00273## 581 306 ##STR00274## 517 307 ##STR00275## 517 308
##STR00276## 531 309 ##STR00277## 531 310 ##STR00278## 311
##STR00279##
##STR00280## Conditions: a) hexamethylditin,
tetrakis(thriphenylphosphine)palladium (0), lithium chloride,
tetrahydrofuran, heat; b) heteroaryl (R2) bromide, palladium
catalyst, dioxane, heat.
Example 197
4-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline
##STR00281##
a) 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline
A mixture of 4-(4-pyridinyl)-6-bromoquinoline (15 g, 53 mmol),
hexamethylditin (19 g, 59 mmol), lithium chloride (16 g, 370 mmol),
tetrakis(triphenyphosphine)-palladium (0) (3 g, 2.7 mmol), in
tetrahydrofuran (400 mL) was heated at reflux for 16 hours, at
which time the reaction was allowed to cool to room temperature and
concentrated under reduced pressure. Methylene chloride (500 mL)
was added to the residue and the mixture was stirred for 2 hours to
help break up the solids. The mixture was then filtered and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (gradient: CH.sub.2Cl.sub.2
to 2% MeOH/CH.sub.2Cl.sub.2) to give the title compound (11 g, 56%)
as a beige solid. MS(ES)+ m/e 370 [M+H].sup.+.
b)
4-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline
A mixture of 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.5
mmol), 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline (204 mg,
0.55 mmol), and tetrakistriphenylphosphine palladium(0) (29 mg,
0.025 mmol) in 1,4-dioxane (3.0 mL) was heated at 100.degree. C.
for 18 h. The reaction was filtered to collect the precipitate. The
solid was triturated in hot ethanol to give an off-white solid,
which still contained some minor impurities. The off-white solid
was triturated in hot ethanol to give the title product as a beige
solid (22 mg, 14%). MS(ES)+ m/e 325.1 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 197:
TABLE-US-00006 MS(ES) Example Structure [M + H].sup.+ 198
##STR00282## 324 199 ##STR00283## 325 200 ##STR00284## 323 201
##STR00285## 324 202 ##STR00286## 379 203 ##STR00287## 381
##STR00288## Conditions: a) diethylethoxymethylene malonate,
140.degree. C., then Dowtherm A, 260.degree. C.; b) 6 N sodium
hydroxide, ethanol, reflux; c) Dowtherm A, 260.degree. C.; d)
phosphorous oxychloride, reflux; e) bis(pinacolato)diboron,
palladium catalyst, potassium acetate, dioxane, heat; then
heteroaryl (R2) bromide, palladium catalyst, 2 M aqueous potassium
carbonate, heat; then aryl (R1) boronic acid/ester, palladium
catalyst, 2 M aqueous potassium carbonate, dioxane, heat.
Example 204
2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridines-
ulfonamide
##STR00289##
a) ethyl 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate
A mixture of 4-bromo-2-methylaniline (1.50 g, 8.04 mmol) and
diethylethoxymethylene malonate (1.74 g, 8.04 mmol) was heated at
140.degree. C. with stirring in an oil bath for 5.0 h. The reaction
was transferred to a heating mantle, diluted with Dowtherm A (4
mL), and heated at 260.degree. C. for 1 h. The reaction was cooled,
diluted with hexanes, and the suspension was stirred overnight at
room temperature. The suspension was filtered and the filtered
solid was washed with hexanes and dried in a Buchner funnel to give
the title compound (1.90 g, 76%) as a tan solid. MS(ES)+ m/e 310
[M+H].
b) 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid
A mixture of ethyl
6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate (1.89 g, 6.09
mmol) and 6 N NaOH (1.22 g, 30.45 mmol, 5.1 mL) in ethanol (30 mL)
was heated at reflux for 2.0 h and concentrated in vacuo. The
residue was diluted with water and acidified with 6 N HCl to pH 4.
The resulting solid was filtered, washed with water and diethyl
ether, and dried overnight in a Buchner funnel to give the title
compound (1.72 g, 99%) as a tan solid. MS(ES)+ m/e 282 [M+H].
c) 6-bromo-8-methyl-4-quinolinol
A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid
(1.80 g, 6.36 mmol) and Dowtherm A (10 mL) was heated at
260.degree. C. for 1.0 h. The reaction was cooled, triturated with
hexanes, filtered and dried in a Buchner funnel to give the title
compound (1.43 g, 95%) as a tan solid. MS(ES)+ m/e 238 [M+H].
d) 6-bromo-4-chloro-8-methylquinoline
A mixture of 6-bromo-8-methyl-4-quinolinol (1.42 g, 5.95 mmol) and
phosphorous oxychloride (10.95 g, 71.40 mmol) was heated at reflux
for 1 h, cooled, poured onto ice, and neutralized by addition of
30% ammonium hydroxide. The resulting solid was filtered and dried
in a vacuum oven to give the title compound (1.45 g, 95%) as a tan
solid. MS(ES)+ m/e 256 [M+H].
e)
2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridi-
nesulfonamide
A mixture of 6-bromo-4-chloro-8-methylquinoline (0.300 g, 1.170
mmol), bis(pinacolato)diboron (0.297 g, 1.170 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.029 g, 0.035 mmol), and solid anhydrous
potassium acetate (0.459 g, 4.676 mmol) in dry 1,4-dioxane (8 mL)
was heated at reflux for 70 minutes. The oil bath was temporarily
removed and to the reaction was added
2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide (0.327 g, 1.17
mmol), dichloro [1,1'-bis(diphenylphosphino)ferrocene]palladium
(II) dichloromethane adduct (0.047 g, 0.058 mmol), and 2 M aqueous
potassium carbonate (0.646 g, 4.676 mmol, 2.34 mL). The reaction
was heated at reflux for 80 minutes. The oil bath was temporarily
removed and to the reaction was added
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.240 g,
1.17 mmol), dichloro
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.047 g, 0.058 mmol), 2 M aqueous potassium
carbonate (0.485 g, 3.51 mmol, 1.76 mL), and 1,4-dioxane (6 mL).
The reaction was heated at reflux for 17 h and concentrated in
vacuo. The residue was triturated with 10% MeOH:EtOAc (45 mL),
filtered through filter paper, and the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel (7% MeOH:EtOAc) to give the title compound (0.135 g, 28%) as a
yellow powder. MS(ES)+ m/e 420 [M+H].
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 204:
TABLE-US-00007 MS(ES) Example Structure [M + H].sup.+ 205
##STR00290## 424 206 ##STR00291## 420 207 ##STR00292## 424 208
##STR00293## 381 209 ##STR00294## 377 210 ##STR00295## 377
##STR00296## Conditions: a) bis(pinacolato)diboron, potassium
acetate, palladium catalyst, dioxane, heat; then
5-bromo-2-pyridinamine, palladium catalyst, 2 M potassium
carbonate, dioxane, heat; b) chlorosulfonic acid, 0.degree.
C.--reflux; c) R.sub.6R.sub.7NH, pyridine, dioxane, rt-50.degree.
C.
Example 211
3-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine
##STR00297##
a) 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine
To a 1 L pressure vessel was added 6-bromo-4-(4-pyridinyl)quinoline
(12 g, 42.08 mmol), bis(pinacolato)diboron (12.8 g, 50.5 mmol),
anhydrous potassium acetate (8.24 g, 84.16 mmol),
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complex
with dichloromethane(1:1) (1.372 g, 1.68 mmol) and anhydrous
dioxane (420 mL). The reaction vessel was purged with nitrogen,
capped and heated at 100.degree. C. for 15 hours. LCMS indicated
96% conversion to a mixture of the desired boronate ester MS(ES)+
m/e 333.2 [M+H].sup.+ and boronic acid MS(ES)+m/e 250.9
[M+H].sup.+.
To the reaction mixture above was added 5-bromo-2-pyridinamine
(7.28 g, 42.08 mmol),
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complex
with dichloromethane(1:1) (1.718 g, 2.1 mmol), 2 M aqueous
K.sub.2CO.sub.3 (300 mL). The reaction was heated at 100.degree. C.
for 21 hours. After cooling to room temperature, the organic layer
was separated and concentrated in vacuo. The residue was triturated
with water, and dissolved in dichloromethane. This solution was
filtered through a plug of silica, washing continuously with
dicholormethane and ethanol. Concentration in vacuo provided the
title compound as a yellow powder (8.767 g, 70% yield). MS(ES)+ m/e
299.0 [M+H].sup.+.
b) 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl
chloride
To cold (0.degree. C.) chlorosulfonic acid (15 mL) under vigorous
stirring was added 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine
(4.348 g, 14.57 mmol) portionwise. The reaction mixture was then
heated at reflux for 16 hrs. Upon cooling to room temperature, LCMS
indicated 47% of the title compound MS(ES)+m/e 396.9 [M+].sup.+ and
37% of sulfonic acid by-product MS(ES)+ m/e 379.1 [M+].sup.+. A 2
mL aliquot of this 0.456M solution of the title compound was used
in the next reaction without further workup.
c)
3-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinami-
ne
To a cold (5.degree. C.) solution of the 0.456 M solution of
2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl
chloride (2 mL, 0.912 mmol) in chlorosulfonic acid from above was
added anhydrous dioxane (1 mL) and piperidine (1.8 mL, 18.24 mmol).
After 30 minutes of stirring, pyridine (1 mL, 12.3 mmol) was added
and the reaction mixture stirred for an additional hour at room
temperature. The reaction mixture was concentrated in vacuo, the
residue dissolved in CH.sub.2Cl.sub.2 and the pH adjusted to 14
using 6 N NaOH (aq). The solution was extracted with
CH.sub.2Cl.sub.2 (.times.4) and the combined organic layers dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
resulting residue was purified twice by silica gel chromatography
(0-5% MeOH in EtOAC) to give the title compound as a pale yellow
solid (269 mg, 66% yield). MS(ES)+ m/e 446.3 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 211:
TABLE-US-00008 MS Ex- (ES) am- [M + ple Structure H].sup.+ 212
##STR00298## 446 213 ##STR00299## 406 214 ##STR00300## 463 215
##STR00301## 469 216 ##STR00302## 454 217 ##STR00303## 453 218
##STR00304## 434 219 ##STR00305## 432
##STR00306## Conditions: a) aryl (R1) boronic acid or aryl (R1)
boronate, palladium catalyst, 2 M potassium carbonate, dioxane,
heat; b) bis(pinacolato)diboron, potassium acetate, palladium
catalyst, dioxane, heat; then heteroaryl (R2) bromide, palladium
catalyst, 2 M potassium carbonate, heat.
Example 220
Preparation of
6-(1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline
##STR00307##
a) 4-(4-pyridinyl)-6-quinolinecarbonitrile
A mixture of 4-chloro-6-quinolinecarbonitrile (8.7 g, 46.2 mmol),
4-pyridineboronic acid (8.52 g, 69.3 mmol),
tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and 2
M potassium carbonate (69.3 mL, 3 eq) in 1,4-dioxane (380 mL) is
heated at reflux for 3.5 hours. The dioxane is evaporated and the
crude product purified by silica gel chromatography eluting with
methylene chloride/methanol 0-4%. A yield of 10.23 g (95%) of the
title compounds was obtained.
b) 1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline
A mixture of 4-(4-pyridinyl)-6-quinolinecarbonitrile, (231 mg, 1
mmol) 1,2-diaminobenzene (108 mg, 1 mmol) and polyphosphoric acid
(1.4 g) was heated in the microwave at 250.degree. C. for 1.5
hours. The reaction was poured onto water which was neutralized
with bicarbonate. The product was filtered, washed with water, and
dried. The product was further purified by dissolving in hot
methanol, filtering and cooling to obtain crystals. The yield was
47.7 mg, 30%. MS(ES)+M/e 323 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 220:
TABLE-US-00009 MS(ES) Example Structure [M + H].sup.+ 221
##STR00308## 323 222 ##STR00309## 324 223 ##STR00310## 324 224
##STR00311## 325
##STR00312## Conditions: a) cyclic secondary amine,
dimethylformamide, heat; b) bis(pinacolato)diboron, potassium
acetate, palladium catalyst, dioxane, heat; then heteroaryl (R2)
bromide, palladium catalyst, 2 M potassium carbonate, heat.
Example 225
4-(1-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
##STR00313##
a) 6-bromo-4-(1-piperidinyl)quinoline
To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL
of 1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol).
The reaction was heated to 150.degree. C. for 5 h. The solvents
were removed in vacuo at 100.degree. C. and the residue dissolved
in methylene chloride and washed with water. The methylene chloride
was dried with sodium sulfate and concentrated. The residue was
triturated with hexane and the solid filtered off to give
6-bromo-4-(1-piperidinyl) quinoline (877 mg, 73%).
b)
6-(7,7a-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(1-piperidinyl)quinol-
ine
To a solution of 6-bromo-4-(1-piperidinyl)quinoline (429 mg, 1.47
mmol) in dioxane (4 mL) was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (373 mg,
1.76 mmol), potassium acetate (441 mg, 4.5 mmol), and
PdCl2(dppf).sub.2 (36 mg, 0.045 mmol). The reaction was heated to
150.degree. C. for 30 minutes to give crude
4-(1-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-
e. The reaction was then cooled and
5-bromo-7,7a-dihydro-1H-pyrazolo[3,4-b]pyridine (348 mg, 1.76 mmol)
was added, followed by PdCl2(dppf).sub.2 (36 mg, 0.045 mmol) and 2
M potassium carbonate (2.25 mL). The reaction was heated at
150.degree. C. for 30 min, at which time the dioxane was evaporated
and the crude product triturated water and collected by filtration.
The crude product was partially purified by HPLC chromatography
acetonitrile/water/0.1% TFA. At this point the product was 85%
pure. It was free based with sodium carbonate and further purified
by silica gel chromatography eluting with methylene chloride/0-2%
(methanol/concentrated ammonium hydroxide solution 9/1) to obtain
the title compound (29 mg, 0 6%). MS(ES)+ m/e 330 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 225:
TABLE-US-00010 MS(ES) Example Structure [M + H].sup.+ 226
##STR00314## 332 227 ##STR00315## 345 228 ##STR00316## 330 229
##STR00317## 332
##STR00318## Conditions: a) R-sulfonyl chloride, pyridine,
methylene chloride.
Example 230
2,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfon-
amide
##STR00319##
a)
2,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesul-
fonamide
A solution of 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine (82
mg, 0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat
2,4-difluorobenzenesulfonyl chloride in one portion. The reaction
was stirred at room temperature for 30 minutes then was purified
directly by prep-HPLC. The combined, desired fractions were
evaporated under reduced pressure to remove organic solvents then
diluted with small portions of brine and saturated aqueous sodium
bicarbonate. The basic solution was extracted with ethyl acetate
then the extracts were dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The resulting colorless film was
crystallized from methylene chloride and diethyl ether. The solids
were collected by filtration, rinsed with diethyl ether then vacuum
dried to afford the title compound (219 mg, 48%) as a white solid.
MS(ES)+ m/e 475 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 230:
TABLE-US-00011 MS(ES) Example Structure [M + H].sup.+ 231
##STR00320## 443 232 ##STR00321## 445 233 ##STR00322## 458 234
##STR00323## 499 235 ##STR00324## 419 236 ##STR00325## 403 237
##STR00326## 439 238 ##STR00327## 453 312 ##STR00328## 457 313
##STR00329## 457 314 ##STR00330## 469 315 ##STR00331## 457 316
##STR00332## 484 317 ##STR00333## 464 318 ##STR00334## 507 319
##STR00335## 507 320 ##STR00336## 440.1 321 ##STR00337## 457.1 322
##STR00338## 511.1 323 ##STR00339## 471.2 324 ##STR00340## 483.1
325 ##STR00341## 406.3 326 ##STR00342## 418.3 327 ##STR00343##
443.2 328 ##STR00344## 498.2 329 ##STR00345## 429 330 ##STR00346##
453 331 ##STR00347## 471.2 332 ##STR00348## 500.3 333 ##STR00349##
547.0, 549.1 334 ##STR00350## 512.2 335 ##STR00351## 498.2 336
##STR00352## 457.1 337 ##STR00353## 525.4 338 ##STR00354## 471.2
339 ##STR00355## 429.1 340 ##STR00356## 457.1 341 ##STR00357## 507
342 ##STR00358## 507 343 ##STR00359## 581.9 344 ##STR00360##
432.2
Some non-commercially available heteroaryl (R1) bromides were
prepared and coupled to the corresponding boronic ester or boronic
acid as noted above.
##STR00361## Conditions: a) Chlorosulfonic acid, 0.degree.
C.--reflux; b) Morpholine, pyridine, dioxane, 5.degree.
C.--rt--50.degree. C.
Example 239
3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine
##STR00362##
a) 2-amino-5-bromo-3-pyridinesulfonyl chloride
To a cooled (0.degree. C.) solution of chlorosulfonic acid (58 mL)
under vigorous stirring was added 5-bromo-2-pyridinamine (15 g,
86.7 mmol) portionwise. The reaction mixture was then heated at
reflux for 3 hrs. Upon cooling to room temperature, the reaction
mixture was poured over ice (p100 g) with vigorous stirring. The
resulting yellow precipitate was collected by suction filtration,
washing with cold water and petroleum ether to provide the title
compound as an orange-yellow solid (18.1 g, 77% yield). MS(ES)+ m/e
272.8 [M+H].sup.+.
b) 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine
To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50
g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5.degree. C.
was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL,
2.15 mmol) of pyridine. The reaction mixture was stirred at room
temperature for 2 hrs and then heated at 50.degree. C. for 1 hour.
After cooling to room temperature, a white precipitate formed which
was collected by suction filtration, washing with water and
petroleum ether to give the title compound as an off-white solid.
(0.539 g, 91% yield). MS(ES)+ m/e 323.9 [M+H].sup.+.
c)
3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinami-
ne
A mixture of 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine
(0.296 g, 0.92 mmol),
4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
(0.306 mg, 0.92 mmol),
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complex
with dichloromethane(1:1) (37.6 mg, 0.046 mmol), 2 M aqueous
K.sub.2CO.sub.3 (5 mL) and dioxane (5 mL) was heated at 100.degree.
C. for 18 h. After cooling to room temperature, the organic layer
was separated and the aqueous portion extracted three times with
EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was purified twice
by silica gel chromatography (eluent: i) 1-5% MeOH in
CH.sub.2Cl.sub.2 and ii) 0-20% MeOH in CH.sub.2Cl.sub.2) to provide
the title compound as a white solid (150 mg, 37% yield). MS(ES)+
m/e 448.0 [M+H].sup.+.
##STR00363## Conditions: a) i) LDA, THF, -78.degree. C.; ii)
N-formylpiperidine, -78.degree. C.; b) i) pinacol, p-TsOH, benzene,
reflux; ii) anhydrous hydrazine, DIPEA, EtOH, reflux; c) conc aq
HCl (36.5%-38%), EtOH, H.sub.2O, 60.degree. C. to rt.
Example 240
5-bromo-1H-pyrazolo[3,4-b]pyridine
##STR00364##
a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde
Following the procedure described in WO2006015124 and trituration
of the crude product in hexanes instead of crystallization from
cyclohexane afforded the title compound as an off-white solid
(68%). MS(ES)+ m/e 203.8, 205.7 [M+H].sup.+.
b)
5-bromo-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2(1H)-pyridinone
hydrazone
Following the procedure described in WO2006015124 without the
addition of hydrogen chloride provided the title compound as a
yellow solid. MS(ES)+ m/e 317.9 [M+H].sup.+. This crude material
was used directly in the next step.
c) 5-bromo-1H-pyrazolo[3,4-b]pyridine
Following the procedure described in WO2006015124 provided the
title compound as a yellow solid (94%, 2 steps). MS(ES)+ m/e 197.7,
199.7 [M+H].sup.+.
##STR00365## Conditions: a) tin(II) chloride, concentrated HCl,
room temperature; b) R-sulfonyl chloride, pyridine, methylene
chloride.
Example 241
N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide
##STR00366##
a) 3-amino-5-bromo-2-chloropyridine
To a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (20.0
g, 84.2 mMol) in conc. HCl (90 mL) was added SnCl.sub.2.2H.sub.2O
(60.0 g, 266 mMol) portionwise over 2 h. (The reaction got very
warm to the touch.) The reaction was stirred at RT for 18 h, poured
onto ice, and basified with aq. 6 N NaOH (300 mL). The resultant
slurry was filtered, washed with H.sub.2O, and dried under vacuum
to give the title compound (15.53 g, 89%) as an off-white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.66 (d, J=2.3 Hz,
1H), 7.30 (d, J=2.3 Hz, 1H), 5.90 (br. s., 2H); MS(ES) m/e 206.7
(M+H).sup.+.
b) N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide
To a stirred solution of 3-amino-5-bromo-2-chloropyridine (5.0 g,
24 mMol) in CH.sub.2Cl.sub.2 (50 mL) was added pyridine (3.0 mL, 37
mMol) followed by benzenesulfonyl chloride (4.5 mL, 35 mMol) drop
wise over 5 minutes. The reaction was stirred at RT for 18 h and
evaporated to dryness under vacuum. Purified by flash
chromatography on silica gel (15% hexanes in CH.sub.2Cl.sub.2 then
0 to 5% EtOAc in 15% hexanes in CH.sub.2Cl.sub.2). During
evaporation of the solvents the product crashed out. The resultant
slurry was diluted with hexane, filtered and dried under vacuum to
give the title compound (2.89 g, 34%) as a white solid. [An overlap
fraction which contained 30% starting amine (2.60 g) was also
obtained.]: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.61
(br. s., 1H), 8.41 (d, J=2.27 Hz, 1H), 7.91 (d, J=2.27 Hz, 1H),
7.73-7.77 (m, 2H), 7.67-7.72 (m, 1H), 7.56-7.64 (m, 2H); MS(ES) m/e
346.7 (M+H).sup.+.
Other non-commercially available heteroaryl (R1) bromides were
prepared according to the following literature procedures and
coupled to the corresponding boronic ester as noted above:
WO2005110410 was used to prepare intermediates A-C.
##STR00367##
##STR00368## Conditions: a) methyl
(triphenylphosphoranylidene)acetate, methanol, rt; b) bromine,
methylene chloride, rt; c) ii potassium hydroxide, ethanol,
95.degree. C.; ii] sulfuric acid, ethanol, 95.degree. C.; d)
potassium tert-butoxide, (R8)-hydrazine, tetrahydrofuran,
rt--65.degree. C.
Example 242
1-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one
##STR00369##
a) methyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propenoate
A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (2.29 g, 9.78
mmol), methyl (triphenylphosphoranylidene)acetate (3.30 g, 9.78
mmol) in MeOH (75 mL) was stirred at room temperature for 1 hour.
The reaction was evaporated under reduced pressure and the
resulting residue was purified by silica gel chromatography (1%
MeOH in EtOAc) to give the title compound (2.71 g, 95%) as a white
solid. MS(ES)+ m/e 291 [M+H].sup.+.
b) methyl
2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate
A solution of methyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propenoate
(2.71 g, 9.33 mmol) in dichloromethane (90 ml) was treated with
neat bromine (4.80 ml, 9.33 mmol) then stirred at room temperature
for 4 hours. Evaporation under reduced pressure gave the title
compound (4.20 g, 100%) as a yellow solid. MS(ES)+ m/e 451
[M+H].sup.+.
c) ethyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate
A slurry of methyl
2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate (4.20 g,
9.33 mmol) in ethanol (120 ml) was treated with solid potassium
hydroxide pellets in one portion then heated at 95.degree. C. for 2
hours. The reaction was cooled to room temperature then evaporated
under reduced pressure. The resulting residue was diluted with
ethanol (90 ml) and concentrated H.sub.2SO.sub.4 (3 ml) then heated
at 95.degree. C. for 3.5 hours. Cooled to room temperature then
concentrated under reduced pressure. The resulting wet residue was
taken into a minimum of water then made neutral with the addition
of saturated aqueous NaHCO.sub.3 solution. This solution was
extracted with EtOAc and the extracts were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
resulting residue was purified by silica gel chromatography (EtOAc)
to give the title compound (1.68 g, 60%) as a pale yellow solid.
MS(ES)+ m/e 303 [M+H].sup.+.
d)
1-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one
A solution of phenylhydrazine (0.093 ml, 0.95 mmol) in anhydrous
THF (4.0 ml) was treated with a 1M solution of potassium
tert-butoxide in THF (1.89 ml, 1.89 mmol). The resulting solution
was added to a solution of ethyl
3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate (0.268 g, 0.95 mmol)
in THF (10 ml). The resulting brown solution was stirred at room
temperature for 1 hour then at 65.degree. C. for 1 hour. The
resulting orange slurry was cooled to room temperature then
concentrated under reduced pressure. The resulting residue was
taken into saturated aqueous NaHCO.sub.3 then extracted into
methylene chloride and the extracts were dried over sodium sulfate
then evaporated under reduced pressure. The resulting oil was
purified by HPLC (acetonitrile/water, 5-80% gradient). The product
was concentrated to a residue then recrystallized from ethanol to
give the title compound (0.020 g, 6%) as a white solid. MS(ES)+ m/e
365 [M+H].sup.+.
The following compounds were or can be prepared following the
general procedures used to prepare the compound of Example 242:
TABLE-US-00012 MS(ES) Example Structure [M + H].sup.+ 243
##STR00370## 379 244 ##STR00371## 399 245 ##STR00372## 289 246
##STR00373## 303
Following the procedure used to prepare Example 242,
2-ethyl-6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-pyrimidinone was or
can be prepared by substituting ethylamidine hydrochloride for
hydrazine. MS(ES)+ m/e 329 [M+H].sup.+.
TABLE-US-00013 MS(ES) Example Structure [M + H].sup.+ 247
##STR00374## 329
Following the procedure used to prepare Example 242,
2-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one
was or can be prepared by substituting an alkynyl methyl ester for
the alkynyl ethyl ester. MS(ES)+ m/e 365 [M+H].sup.+.
TABLE-US-00014 MS(ES) Example Structure [M + H].sup.+ 248
##STR00375## 365
##STR00376## Conditions: a) aryl (R1) stannane, palladium catalyst,
dioxane, heat; b) bis(pinacolato)diboron, potassium acetate,
palladium catalyst, dioxane, heat; then heteroaryl (R2) bromide,
palladium catalyst, saturated aqueous Na.sub.2CO.sub.3, dioxane,
heat.
Example 345
2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridin-
yl}benzenesulfonamide
##STR00377##
a) 6-bromo-4-(4-pyridazinyl)quinoline
Dissolved 6-bromo-4-iodoquinoline (17.43 g, 52.2 mmol),
4-(tributylstannanyl)pyridazine (19.27 g, 52.2 mmol), and
PdCl2(dppf)-CH2Cl2 (2.132 g, 2.61 mmol) in 1,4-dioxane (200 mL) and
heated to 105.degree. C. After 3 h, added more palladium catalyst
and heated for 6 h. Concentrated and dissolved in methylene
chloride/methanol. Purified by column chromatography (combiflash)
with 2% MeOH/EtOAc to 5% MeOH/EtOAc to give the crude title
compound. Trituration with EtOAc furnished
6-bromo-4-(4-pyridazinyl)quinoline (5.8 g, 20.27 mmol, 38.8%
yield). MS(ES)+ m/e 285.9, 287.9 [M+H].sup.+.
b)
2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyri-
dinyl}benzenesulfonamide
A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 mmol),
bis(pinacolato)diboron (4.69 g, 18.45 mmol), PdCl2(dppf)-CH2Cl2
(530 mg, 0.649 mmol) and potassium acetate (3.29 g, 33.6 mmol) in
anhydrous 1,4-dioxane (120 ml) was heated at 100.degree. C. for 3
h. The complete disappearance of the starting bromide was observed
by LCMS. The reaction was then treated with
N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide
(6.68 g, 17.61 mmol) and another portion of PdCl2(dppf)-CH2Cl2 (550
mg, 0.673 mmol), then heated at 110.degree. C. for 16 h. The
reaction was allowed to cool to room temperature, filtered, and
concentrated. Purification of the residue by chromatography
(Analogix; 5% MeOH/5% CH2Cl2/90% EtOAC) gave 6.5 g (76%) desired
product. MS(ES)+ m/e 505.9 [M+H].sup.+.
The following examples were or can be prepared following the
general procedure used in Example 345
TABLE-US-00015 MS(ES) Example Structure [M + H].sup.+ 346
##STR00378## 474 347 ##STR00379## 476 348 ##STR00380## 510
Intermediates: Intermediate 1
##STR00381## Conditions: a) Tributyl(vinyl)tin,
Pd(PPh.sub.3).sub.4, dioxane, reflux; b) OsO.sub.4, NaIO.sub.4,
2,6-lutidine, t-BuOH, dioxane, H.sub.2O, rt; c) (4-pyridyl)boronic
acid, Pd(PPh.sub.3).sub.4, 2 M K.sub.2CO.sub.3, DMF, 100
.quadrature.C.
4-(4-pyridinyl)-6-quinolinecarbaldehyde
##STR00382##
a) 4-chloro-6-ethenylquinoline
A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J.
Med. Chem., 21, 268 (1978)), tributyl(vinyl)tin (8.95 g, 28.22
mmol), and tetrakistriphenylphosphine palladium (0) (0.62 g, 0.54
mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to
room temperature, and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (0-4%
MeOH:CH.sub.2Cl.sub.2) to give the title compound (5.1 g) as a pale
yellow solid. MS(ES)+m/e 190 [M+H].sup.+. This material was used
directly in the next step.
b) 4-chloro-6-quinolinecarbaldehyde
A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol),
2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99
g, 107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution in
tert-butanol, 0.538 mmol) in 1,4-dioxane:H.sub.2O (350 mL of 3:1
mixture) was stirred for 3.5 h at room temperature and concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel (CH.sub.2Cl.sub.2) to give the title compound (4.26 g,
83% for 2 steps) as a pale yellow solid. MS (ES)+ m/e 192
[M+H].sup.+.
c) 4-(4-pyridinyl)-6-quinolinecarbaldehyde
A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol),
4-pyridylboronic acid (3.12 g, 25.38 mmol),
tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and
2M aqueous K.sub.2CO.sub.3 (7.02 g, 50.76 mmol, 25.4 mls of 2M
solution) in DMF (100 mL) was heated at 100.degree. C. for 3.0 h
and cooled to room temperature. The mixture was filtered through
Celite and the Celite was washed with EtOAc. The filtrate was
transferred to a separatory funnel, washed with water and saturated
NaCl, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel (5%
MeOH:CH.sub.2Cl.sub.2) to give the title compound (2.03 g, 51%) as
a tan solid. MS(ES)+ m/e 235 [M+H].sup.+.
Intermediate 2
Preparation of
2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide
##STR00383##
a) 2-amino-5-bromo-3-pyridinesulfonyl chloride
To a cooled (0.degree. C.) solution of chlorosulfonic acid (58 mL)
under vigorous stirring was added 5-bromo-2-pyridinamine (86.7
mmol) portionwise. The reaction mixture was then heated at reflux
for 3 hrs. Upon cooling to room temperature, the reaction mixture
was poured over ice (.about.100 g) with vigorous stirring. The
resulting yellow precipitate was collected by suction filtration,
washing with cold water and petroleum ether to provide the title
compound as an orange-yellow solid (18.1 g, 77% yield). MS(ES)+ m/e
272.8 [M+H].sup.+.
*Other sulfonyl chlorides can be prepared using this procedure by
varying the choice of substituted aryl or heteroaryl.
b) 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide
To a cold (0 .quadrature.C) suspension of
2-amino-5-bromo-3-pyridinesulfonyl chloride (92.1 mmol) in dry
1,4-dioxane (92 mL) was added pyridine (101.3 mmol) followed by a
2M solution of dimethylamine in THF (101.3 mmol). The reaction was
allowed to warm to rt for 2 h, heated to 50 .quadrature.C for 1 h,
then cooled to rt. After standing for 2 h, the precipitate was
collected by filtration and rinsed with a minimal amount of cold
water. Drying the precipitate to constant weight under high vacuum
provided 14.1 g (55%) of the title compound as a white solid.
MS(ES)+ m/e 279.8, 282.0 [M+H].sup.+.
*Other sulfonamides were or can be prepared using this procedure by
varying the choice of sulfonyl chloride and amine.
##STR00384## ##STR00385## Intermediate 3
Preparation of
2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-py-
ridinesulfonamide
##STR00386##
c) To a solution of
2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide (7.14 mmol) in
1,4-dioxane (35 mL) was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (7.86
mmol), potassium acetate (28.56 mmol) and
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
dichloromethane complex (1:1) (0.571 mmol). The reaction mixture
was stirred at 100.degree. C. for 18 h. The reaction was
concentrated in vacuo, re-dissolved in ethyl acetate (50 mL) and
purified on silica using 60% ethyl acetate/hexanes to yield the
title compound as a tan solid (86%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.41 (d, 1H, J=1.52), 7.92 (d, 1H,
J=1.77), 2.68 (s, 6H), 1.28 (s, 12H).
*Other boronate or boronic acids can be prepared using this
procedure by varying the choice of aryl or heteroaryl bromide.
##STR00387## Conditions: a) NaO(R1), (R1)OH, 0.degree. C. to room
temperature; b) SnCl.sub.2.2H.sub.2O, ethyl acetate, reflux; c)
(R2)SO.sub.2Cl, pyridine, 0.degree. C. to room temperature.
Intermediate 4
Preparation of
N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide
##STR00388##
a) 5-bromo-2-(methyloxy)-3-nitropyridine
To a cooled (0.degree. C.) solution of
5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200
mL) was added dropwise over 10 minutes 20% sodium methoxide (50 mL,
211 mmol) solution. The reaction, which quickly became
heterogeneous, was allowed to warm to ambient temperature and
stirred for 16 h. The reaction was filtered and the precipitate
diluted with water (200 mL) and stirred for 1 h. The solids were
filtered, washed with water (3.times.100 mL) and dried in a vac
oven (40.degree. C.) to give 5-bromo-2-(methyloxy)-3-nitropyridine
(36 g, 154 mmol, 73.4% yield) as a pale yellow powder. The original
filtrate was concentrated in vacuo and diluted with water (150 mL).
Saturated ammonium chloride (25 mL) was added and the mixture
stirred for 1 h. The solids were filtered, washed with water, and
dried in a vac oven (40.degree. C.) to give a second crop of
5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34%
yield). Total yield=90%. MS(ES)+ m/e 232.8, 234.7 [M+H].sup.+.
b) 5-bromo-2-(methyloxy)-3-pyridinamine
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193
mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate
(174 g, 772 mmol). The reaction mixture was heated at reflux for 4
h. LC/MS indicated some starting material remained, so added 20 mol
% tin (II) chloride dihydrate and continued to heat at reflux.
After 2 h, the reaction was allowed to cool to ambient temperature
and concentrated in vacuo. The residue was treated with 2 N sodium
hydroxide and the mixture stirred for 1 h. The mixture was then
with methylene chloride (1 L), filtered through Celite, and washed
with methylene chloride (500 mL). The layers were separated and the
organics dried over magnesium sulfate and concentrated to give
5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7% yield).
The product was used crude in subsequent reactions. MS(ES)+ m/e
201.9, 203.9 [M+H].sup.+.
c)
N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide
To a cooled (0.degree. C.) solution of
5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in pyridine
(200 mL) was added slowly 2,4-difluorobenzenesulfonyl chloride
(21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The
ice bath was removed and the reaction was stirred at ambient
temperature for 16 h, at which time the reaction was diluted with
water (500 mL) and the solids filtered off and washed with copious
amounts of water. The precipitate was dried in a vacuum oven at
50.degree. C. to give
N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide
(12 g, 31.6 mmol, 31.7% yield) MS(ES)+ m/e 379.0, 380.9
[M+H].sup.+.
*Other N-[5-bromo-2-(alkoxy)-3-pyridinyl]sulfonamides were or can
be prepared using this procedure by varying the choice of sulfonyl
chloride and alkoxide.
##STR00389##
Exemplary Capsule Composition
An oral dosage form for administering the present invention is
produced by filing a standard two piece hard gelatin capsule with
the ingredients in the proportions shown in Table I, below.
TABLE-US-00016 TABLE I INGREDIENTS AMOUNTS compound of example 1 25
mg Lactose 55 mg Talc 16 mg Magnesium Stearate 4 mg
Exemplary Injectable Parenteral Composition
An injectable form for administering the present invention is
produced by stirring 1.5% by weight of compound of example 1 in 10%
by volume propylene glycol in water.
Exemplary Tablet Composition
The sucrose, calcium sulfate dihydrate and an PI3K inhibitor as
shown in Table II below, are mixed and granulated in the
proportions shown with a 10% gelatin solution. The wet granules are
screened, dried, mixed with the starch, talc and stearic acid;
screened and compressed into a tablet.
TABLE-US-00017 TABLE II INGREDIENTS AMOUNTS compound of example 1
20 mg calcium sulfate dehydrate 30 mg Sucrose 4 mg Starch 2 mg Talc
1 mg stearic acid 0.5 mg
While the preferred embodiments of the invention are illustrated by
the above, it is to be understood that the invention is not limited
to the precise instructions herein disclosed and that the right to
all modifications coming within the scope of the following claims
is reserved.
* * * * *